Lucentis and Avastin: A New Era in Treatment

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1 Lucentis and : A New Era in Treatment Abdhish R. Bhavsar, MD Director of Clinical Research, Retina Center, PA Past Chair, Phillips Eye Institute Minneapolis, Minnesota Financial Disclosure: Abdhish R. Bhavsar, MD -Principal Investigator, Phase II FOCUS Trial, Phase III MARINA Trial RAPTR, DRCR LRT Trials -Consultant to Genentech, Eyetech, Novartis FDA Approved Anti-VEGF Treatments Anti-VEGF inhibitors Aptamer: Pegaptanib sodium (Macugen) Antibody fragment: (Lucentis ) Antibody full length: Bevacizumab () Off Label Discussion Anti-VEGF inhibitors Bevacizumab () (Lucentis)/ Bevacizumab () Vein occlusions: CRVO, BRVO Diabetic retinopathy: DME, PDR NVG What Is Angiogenesis? Angiogenesis is the process by which capillaries sprout from existing blood vessels, and it is required for a variety of conditions Normal: menstrual cycle, pregnancy Corrective: wound healing/bone repair New vessel growth p MI Pathologic: vascularization, growth, metastasis e.g., cancer, AMD Angiogenesis: A Balanced Process Angiogenesis and vascular maintenance are regulated by a balance of angiogenesis activators and inhibitors. Selected Angiogenesis Activators and Inhibitors Activators Inhibitors Angiopoietins and 2 Angiostatin Tie-2 Endostatin Alpha- integrins Interferons-,, and Matrix metalloproteinases Interleukins-4, 2, and 8 Nitric oxide Platelet factor 4 COX-2 SPARC fragment TGF- and receptors TIMPS VEGF and receptors Vasostatin Calreticulin TMc 23-8 /6/2 :4:6 AM

2 Angiogenesis: Cascade of Events Vascular Endothelial Growth Factor (VEGF) Secreted endothelial cell mitogen and angiogenic factor regulated by hypoxia Major regulator of physiologic and pathologic angiogenesis important during growth and development (VEGF knockout, even partial, is embryonically lethal) role in tumor angiogenesis Enhances vascular permeability first identified as a vascular permeability factor VEGF Is a Key Mediator of Vascular Permeability and Angiogenesis Upstream activators of VEGF synthesis Downstream signaling pathways Evidence That VEGF Is a Required Angiogenic Growth Factor VEGF antagonists block Embryonic development Bone morphogenesis Female reproductive cycling Corneal angiogenesis Growth of several tumor types in animal models VEGF Elevated in Ophthalmic Disease 994 Aiello Ferrara et al. NEJM paper describing elevated VEGF in several retinal disorders. New England Journal of Medicine. 33(22):48-7, 994 Dec. VEGF in Ocular Neovascularization VEGF fundamental to retinal neovascularization (Aiello et al, 99) VEGF intravitreal injection in normal eyes leads to iris and retinal neovascularization (Adamis et al, 998) high vitreous VEGF levels in eyes with CNV (Wells & Gregor 996) and high VEGF levels in excised human choroidal neovascular membranes (Lopez et al, 998) VEGF overexpression demonstrated in a primate laser retinal injury model of choroidal neovascularization VEGF correlated with active retinal neovascularization in retinopathy of prematurity and proliferative diabetic retinopathy TMc 23-8 /6/2 :4:6 AM 2

3 VEGF as a Therapeutic Target in the Eye VEGF is secreted, freely diffusible, and mitogenic for endothelial cells Multiple retinal cell types make VEGF Retinal endothelial cells have receptors for VEGF Blood-retinal barrier breakdown is both prevented and reversed through VEGF inhibition Extensive data support the role of VEGF in ocular neovascularization & vascular permeability Ferrara et al. Endocr Rev. 992 ; Qaum e al. IOVS. 2 Amano et al. IOVS. 998; Adamis et al. Arch Ophthalmol. 996; Aiello et al, Proc Natl Acad Sci USA. 99; Krzystolik et al. Arch Ophthalmol. 22. VEGF Isoforms in the Human VEGF (VEGF [A]) is a single gene that codes for multiple protein isoforms (defined as a related protein) Isoforms differ in expression patterns and biological/biochemical properties Pathologic Physiologic The human VEGF isoforms are: 2, 4, 6, 89, and 26 The isoform number refers to the number of amino acids contained in the mature, secreted protein Robinson, Stringer. J Cell Sci. 2; Neufeld et al. Faseb J Anti-VEGF Inhibition of Ocular Neovascularization VEGF inhibition using intravitreal antibody injection prevents experimental iris neovascularization VEGF inhibition using intravitreal soluble receptors or antisense oligonucleotides markedly reduces retinal neovascularization VEGF isoforms VEGF gene produces alternatively spliced mrna variants aa aa 6 aa 2 aa T Usui et al. Invest Ophthalmol Vis Sci 24 Feb;4(2): VEGF isoforms VEGF is a cleavage product Soluble and bioactive form of VEGF Biologically similar to VEGF 2 Heparin-binding domain Plasmin 6 6 VEGF-receptor binding site VEGF 6 VEGF Anti-VEGF Antibodies rhumab VEGF full-length humanized monoclonal antibody: 2 antigen binding regions and a complement binding (Fc) region completed Phase III trials for cancer Bevacizumab: rhufab V2 second generation antibody with higher VEGF affinity Fab= antibody fragment: one antigen binding region, no Fc region fully penetrates retina and reaches choroid after intravitreal injection : Lucentis Ruckmann, et al. J Biol Chem. 998;273: TMc 23-8 /6/2 :4:6 AM 3

4 Molecule Structure: rhumab VEGF and rhufab V2 rhufab V2 Showing Mutations that Enhance Affinity for VEGF IgG MW KD Fab MW 48 KD Journal of Molecular Biology 293, 86 (999) Monoclonal Antibody A.4.6. Lucentis Summary Humanization Fab fully penetrates the Retina Herceptin Kim Ferrara Nature 362, (993) Preparing Fab Monoclonal Antibody Human Lucentis Monoclonal Antibody Mouse Humanized Antibody Improved Version V -> V2 Presta Ferrara Cancer Res. 47: Fab MW 48, Fab IgG IgG MW 48, Chen, et al. Journal of Molecular Biology, Vol. 293, No. 4( 86-88) Nov 999 Chen, et al. Journal of Molecular Biology, Vol. 293, No. 4( 86-88) Nov 999 Lucentis penetrates through all retinal layers while IgG only penetrates superficially. Mordenti et al. Toxicologic Pathology. 27():36-44, 999 Sep-Oct. Lucentis What it does: VEGF binds receptors Vascular LEAKAGE and and swelling ANGIOGENESIS Lucentis blocks VEGF Decreased LEAKAGE and and swelling Blocks ANGIOGENESIS Lucentis Binds all VEGF isoforms Lucentis VEGF VEGF VEGF VEGF VEGF VEGF VEGF VEGF Lucentis Lucentis binds near AA 8 thus it can inactivate all isoforms of VEGF (, 2, 6, 89,26) Chen et al. J Mol Biol 293: TMc 23-8 /6/2 :4:6 AM 4

5 Rationale Phase III Program Program consists of one MC/O and one PC trial VEGF expression is elevated in AMD and thought to be responsible for Vascular proliferation Vascular leakage rhufab V2 is a recombinant humanized Fab fragment that has been optimized to avidly bind and inactivate VEGF VEGF rhufab V2 Chen, et al. Journal of Mol. Biol., Vol. 293, No. 4(86-88) Nov 999 Injection Reading Center Study 298 Min Classic/Occult Randomized :: 3 ug rhufab V2 ug rhufab V2 N = monthly intravitreal injections File with % losing < letters at 2 months Study 287 Verteporfin Injection Reading Center Predom Classic Randomized :: 3 ug rhufab V2 ug rhufab V2 N = monthly intravitreal injections File with % losing < letters at 2 months Phase Ic Lucentis TM and Verteporfin combination Rx in PC Study 2428 Injection Predom/Classic Randomized :2 Day prn q3 mos ug Lucentis TM prn q3 mos (Investigator determination) N = monthly intravitreal injections File with safety & tolerability and % losing < letters at 2 mos Randomized, Controlled Phase III Study of for Intravitreal Injection for Minimally Classic or Occult Neovascular AMD: Two-Year Results of the MARINA Study Abdhish R. Bhavsar, MD Study Design and Objectives Phase III, randomized, multi-center, doublemasked, sham-controlled study Evaluation of the efficacy and safety of the investigational drug ranibizumab in subjects with minimally classic or occult with no classic subfoveal choroidal neovascularization (CNV) secondary to AMD Trial Design Investigator identifies potential subjects Reading center confirms angiographic eligibility Minimally classic or occult with no classic lesions (N=76) Randomization ::.3 mg. mg (n=24) TMc 23-8 /6/2 :4:6 AM

6 Treatment Schedule: First Subject Randomized 3/3 Last Subject Visit 2/ Month. mg Primary Endpoint Proportion of subjects who lose < letters at month 2 compared with baseline in the best corrected visual acuity (VA) score.3 mg Primary Endpoint at investigator discretion if: Conversion to predominantly classic CNV, or Loss of 2 letters on 2 consecutive visits and small ( 4 DA), minimally classic or occult with no classic lesions, with presumed recent disease progression Final visit October 2 All subjects offered ranibizumab 2 subjects crossed over at Month 22 or 23 Key Secondary Endpoints Month 2 and Month 24 Visual acuity Proportion gaining letters in VA Mean change from baseline in VA over time Proportion with 2/2 Snellen VA or worse Proportion losing < letters (at Month 24) Anatomy Mean change from baseline in the total area of CNV Mean change from baseline in the total area of leakage* from CNV Principal Eligibility Criteria: Study Eye Age years VA (Snellen equivalent) 2/4 to 2/32 Subfoveal CNV secondary to AMD No prior Lesion composition by fluorescein angiography Area of CNV must be % of total lesion Minimally classic or occult with no classic Evidence of presumed recent disease progression Blood, recent growth by FA, or recent VA loss Lesion size 2 disc areas (DA) *Includes intense, progressive staining of RPE (leaking fibrovascular pigment epithelial detachment) Efficacy*: Through Month 24 * Analyzed based on the intent-to-treat population (ITT) with the last observation carried forward (LOCF) for missing data. Primary Endpoint*: Subjects Losing < Letters from Baseline % of subjects % 9% 9% Month 2 Month 24 *Month 2 was the primary endpoint, month 24 was a secondary endpoint. P<. vs sham.3 mg. mg (n=24) TMc 23-8 /6/2 :4:6 AM 6

7 Primary Endpoint*: Subjects Losing < Letters from Baseline % of subjects % 9% 9% 3% 92% 9% Month 2 Month 24 *Month 2 was the primary endpoint, month 24 was a secondary endpoint. P<. vs sham.3 mg. mg (n=24) Secondary Endpoint: Subjects Gaining Letters from Baseline % of subjects *P<. vs sham % 34%* 2%* 26%* 4% Month 2 Month 24.3 mg. mg (n=24) 33%* Exploratory Endpoint: Subjects Gaining 3 Letters from Baseline % of subjects % 3%* 4% % 6%.4% Month 2 Month 24.3 mg. mg (n=24) % of subjects Exploratory Endpoint: Subjects with VA 2/4 or Better % % % Baseline % 39%* 4%* 6% 34%* 42%* Month 2 Month 24.3 mg. mg (n=24) *P=.8, P=.2, P=., P =.7 vs sham *P<. vs sham Secondary Endpoint: Mean Change in Visual Acuity Over Time.3 mg. mg (n=24) Secondary Endpoint: Mean Change in Visual Acuity Over Time.3 mg. mg (n=24) ETDRS letters letter difference* 6.9 letter difference* ETDRS letters letter difference* 2.3 letter difference* - Month *P<. - Month -4.9 *P<. (Rounded values) Note: Vertical bars are ± one standard error of the mean. Note: Vertical bars are ± one standard error of the mean. TMc 23-8 /6/2 :4:6 AM 7

8 Key Ocular Serious Adverse Events Safety: Through Month 24 (n=236) Cumulative through month 2.3 mg. mg (n=239) (n=236) Cumulative through month 24.3 mg. mg (n=239) Presumed Endophthalmitis Culture Positive Culture Negative 2 (.8%) * (.4%) 3(.3%) * Culture Not Done (.4%) (.4%) Uveitis 2 (.8%) (.4%) 3 (.3%) 3(.3%) Rheg. Retinal Detachment (.4%) Retinal Tear (.4%) (.4%) (.4%) (.4%) Vitreous Hemorrhage (.4%) (.4%) 2 (.8%) (.4%) (.4%) Lens Damage (.4%) (.4%) * One case was reported as uveitis by investigator; One subject had 2 episodes. Cumulative through month 24 non-serious AE of retinal tear in 7 subjects: 2 (), 2 (.3 mg) and 3 (. mg). Year Year 2 Total deaths in study Deaths out of study (n=236) Deaths.3mg (.4%) Myocardial infarction () 6 (2.%) CVA* (2) Unknown cause () CHF () Renal failure () Respiratory failure () 4 (.7%) Myocardial infarction () Unknown cause () NHL complications () Pneumonia (). mg (n=239) 2 (.8%) Small bowel infarct () Chronic asthma/copd () 4 (.7%) CVA* () Hemorrhagic CVA* () MVA head injury () Sepsis () 6 (2.%) (2.%) 6 (2.%) (.4%) Cardiac arrest days after completing month 24 (.4%) Dropped out days after month 22 (subject s decision). Died of lung cancer 4 months after dropout (.4%) Dropped out 3 days after month 23 (Lost to follow-up). Died of lung cancer 2 months after dropout. *CVA=cerebrovascular accident; CHF=congestive heart failure; NHL=Non-Hodgkin s lymphoma; MVA=motor vehicle accident; Key Systemic Findings: Cumulative Through Month 24 (n=236).3 mg. mg (n=239) Hypertension adverse event 38 (6.%) 4 (7.2%) 39 (6.3%) Blood Pressure (mm Hg) Baseline mean SBP/DBP 38/77 37/77 4/76 Month 24 mean SBP/DBP 3/74 3/74 36/7 Mean change in SBP/DBP -3/-4-3/-3-4/- Proteinuria adverse event Nonocular Hemorrhagic adverse Rounded values event * 3 (.%) 22 (9.2%) 2 (8.8%) *Examples include epistaxis, hematoma, ecchymosis, rectal hemorrhage, hematuria, vaginal hemorrhage, GI hemorrhage, etc. Antiplatelet Trialists Collaboration (APTC)* Arterial Thromboembolic Events Used during FDA Cox-2 Inhibitor Advisory Panel Meetings Feb Non-fatal myocardial infarction Non-fatal stroke Ischemic Hemorrhagic Vascular death (from any potential vascular or unknown cause) *Antiplatelet Trialists Collaboration. BMJ. 994 Jan 8;38(692):8-6. Antiplatelet Trialists Collaboration (APTC) Arterial Thromboembolic Events (ATEs) (n=236) Cumulative through month 2*.3 mg. mg (n=239) (n=236) Cumulative through month 24.3 mg. mg (n=239) Vascular deaths (.4%) (.4%) 4 (.7%) 3 (.3%) 3 (.3%) Nonfatal myocardial infarction (.4%) 2 (.8%) (.4%) 4 (.7%) 6 (2.%) 3 (.3%)** Nonfatal ischemic stroke (.4%) (.4%) 3 (.3%) 2 (.8%) 3 (.3%), (2.%) Nonfatal hemorrhagic stroke (.4%)** Total 2 (.8%) 4 (.7%) (2.%) 9 (3.8%) (4.6%) * Based on the study final database One subject had a prior non-fatal ischemic stroke, then a fatal stroke One subject had a nonfatal ischemic stroke and died later of unknown cause One subject had two events of nonfatal myocardial infarction ** One subject had a non-fatal myocardial infarction and a non-fatal hemorrhagic stroke One subject had a non-fatal ischemic stroke in year and a transient ischemic attack in year 2 that progressed to a stroke after month 24 visit. (4.6%) TMc 23-8 /6/2 :4:6 AM 8

9 Systemic Immunoreactivity Time Point Screening Month 6 Month 2 Month 24 (n=236) /2 (.%) 3/2 (.%) 4/26 (.9%) 2/82 (.%).3 mg 2/2 (.9%) 3/2 (.4%) 6/222 (2.7%) 9/26 (4.4%). mg (n=239) /28 (%) 3/27 (.4%) 4/28 (.8%) 3/28 (6.3%) Systemic Immunoreactivity: Subgroup Analysis Based on Immunoreactivity to Efficacy: No association with outcomes Proportion losing < letters Mean VA change Safety: No association with outcomes Intraocular inflammation: AE, SAE, slit lamp Other potential ocular immune AE or SAE e.g. Dry eye, eyelid edema, contact dermatitis Nonocular potential immune AE or SAE e.g. Pruritis, rash, arthralgias Conclusions: Cumulative Data Through Month 24 Efficacy Effect maintained over 2 years (visual acuity, FA) Difference between ranibizumab and sham increases over 2 years Safety No imbalance in deaths between sham and ranibizumab groups Low rate of ocular serious adverse events Presumed endophthalmitis (.3%) and uveitis (.3%) Low rate of nonocular serious adverse events Similar rates of APTC ATEs observed in sham (3.8%) and ranibizumab.3 mg (4.6%) and. mg (4.6%) groups Immunoreactivity Low rate of immunoreactivity observed at 24 months No apparent association with efficacy or safety outcomes A Phase III Study of (Lucentis ) vs Verteporfin (Visudyne ) in Predominantly Classic Subfoveal Neovascular AMD Year Results Study Design and Objectives Phase III, randomized, multi-center, doublemasked, active treatment-controlled study Comparison of efficacy and safety of the investigational drug ranibizumab with verteporfin in subjects with predominantly classic, subfoveal CNV due to AMD Primary Endpoint Proportion of subjects* who lose < letters at month 2 compared with baseline in the best corrected VA score *Intent to treat population with last observation carried forward TMc 23-8 /6/2 :4:6 AM 9

10 Key Secondary Endpoints Proportion of subjects who gain letters in VA at month 2 compared with baseline Proportion of subjects with a VA of 2/2 or worse at month 2 Mean change from baseline in VA over time up to month 2 Principal Eligibility Criteria Study Eye Age years VA (Snellen equivalent) 2/4 to 2/32 Primary or recurrent subfoveal CNV* lesion secondary to AMD in the study eye No prior Lesion composition by fluorescein angiography Classic CNV % of the total lesion area (predominantly classic lesion) Total lesion 4 µm in greatest linear dimension * CNV lesion is defined as CNV detectable by FA plus any associated subretinal hemorrhage, serous PED, fibrosis or other blocked fluorescence Trial Design Treatment Schedule: Year Investigator identifies potential subjects Reading Center confirms angiographic eligibility Predominantly classic lesions (n=423) Month Group Group * * * * * * * * Randomized :: Verteporfin injection (n=43).3 mg (n=4). mg (n=4) Group 3.3 mg ranibizumab * * * * Primary endpoint. mg ranibizumab injection * or when CNV fluorescein leakage Subject Demographics and Baseline Characteristics (n=43).3 mg (n=4). mg (n=4) Gender (% women).2% 47.9% 46.4% Race (% white) 97.9% 97.9% 97.% Age (mean years) Mean VA (letter score) Mean VA (~Snellen equivalent) 2/2 + 2/2 +2 2/2 +2 CNV classification Predominantly classic 98.6% 9.7% 96.4% Minimally classic.4% 3.6% 3.6% Occult.7% Mean lesion size (DA) % of Subjects Primary Endpoint: Subjects Losing < Letters from Baseline at Month % (n=43) 94.3 %* 96.4 %*.3 mg (n=4). mg (n=39) *P <. vs. TMc 23-8 /6/2 :4:6 AM

11 Secondary Endpoint: Letter Gain from Baseline at Month 2 % of Subjects % (n=43) 3.7 %*.3 mg (n=4) 4.3 %*. mg (n=39) *P <. vs. % of Subjects Secondary Endpoint: VA of 2/2 or Worse at Month % (n=43) 6. % 2. % 22.%* 23.%.3 mg (n=4) *P <. vs.. mg (n=4) 6.4%* Baseline Month 2 Baseline Month 2 Baseline Month 2 Secondary Endpoint: Mean Change in Visual Acuity Over Time Secondary Endpoint: Mean Change in Visual Acuity Over Time (n=43) (n=43).3 mg (n=4). mg (n=39) ETDRS letters ETDRS letters letter difference* 8. letter difference* - Month - Month * P <. Note: Vertical bars are ± one standard error of the mean. Note: Vertical bars are ± one standard error of the mean. % of Subjects Other Visual Outcome: VA 2/4 or Better at Month 2. % 2.8 %.4 % 4.3% (n=43).3 mg (n=4) 3.4 %* *P <. vs.. mg (n=4) 38.6%* Baseline Month 2 Baseline Month 2 Baseline Month 2 Other Visual Outcome: 3 Letter Gain from Baseline at Month 2 % of Subjects % (n=43) 6.4 %*.3 mg (n=4) 2.2 %. mg (n=39) *P =.8 vs. P <. vs. TMc 23-8 /6/2 :4:6 AM

12 Other Visual Outcome: 3 Letter Loss from Baseline at Month % of Subjects % (n=43) 2 %* %*.3 mg (n=4). mg (n=39) *P <. vs. % of Subjects Pre-Specified Subgroup Analyses: Subjects Losing < Letters from Baseline at Month 2 82 % % % % %* % % % % 49 n= <4 letter score (worse than 2/2) % ³4 letters (2/2 or better) 44 % Predominantly classic with occult 67% Predominantly classic no occult * P =.8; P <.; P <.; P <. vs. Year Safety Results Key Ocular Serious Adverse Events (n=43).3 mg (n=37). mg (n=4) Presumed Endophthalmitis* Culture Positive Culture Not Done (.7%) (.7%) Uveitis (.7%) Rheg. Retinal Detachment (.7%) (.7%) Retinal Tear Vitreous Hemorrhage (.7%) Lens Damage *Defined as cases in which intravitreal or systemic antibiotics were administered. Same subject had 2 episodes each reported as uveitis. Received systemic antibiotics once. Same subject had 2 episodes. Intraocular Inflammation: Slitlamp Examination Most severe inflammation observed in year (regardless of cause) (n=43).3 mg (n=37). mg (n=4) None 38 (96.%) 2 (87.6%) 6 (82.9%) Trace 4 (2.8%) (8.%) 3 (9.3%) + (.7%) 3 (2.2%) 8 (.7%) 2+ (.7%) (.7%) 3+ 2 (.%) (.7%) 4+ (.7%) Key Systemic Adverse Events (n=43).3 mg (n=37). mg (n=4) Hypertension 2 (8.4%) 3 (2.2%) 9 (6.4%) Mean change in SBP/DBP (mmhg). /.3-2 / -2-2 / Death 2 (.4%) 3 (2.2%) 2 (.4%) Cause of death Cardiac arrest COPD Cardiac arrest Resp arrest Viral syndrome Cardiac failure Chronic heart failure TMc 23-8 /6/2 :4:6 AM 2

13 Antiplatelet Trialists Collaboration (APTC)* Arterial Thromboembolic Events Used during FDA Cox-2 Inhibitor Advisory Panel Meetings Feb Non-fatal myocardial infarction Non-fatal stroke Ischemic Hemorrhagic Vascular death (from any potential vascular or unknown cause) Antiplatelet Trialists Collaboration (APTC)* Arterial Thromboembolic Events Vascular Death Nonfatal Myocardial Infarction Nonfatal Ischemic Stroke Nonfatal Hemorr. Stroke Total Serious adverse events (n=43) (.7%) (.7%) (.7%) 3 (2.%).3 mg (n=37) (.7%) (.7%) (.7%) 3 (2.2%). mg (n=4) 2 (.4%) 3 (2.%) (.7%) 6 (4.3%) *Antiplatelet Trialists Collaboration. BMJ. 994 Jan 8;38(692):8-6. *Antiplatelet Trialists Collaboration. BMJ. 994 Jan 8;38(692):8-6. Conclusions: 2 Month Safety Low rate of ocular serious adverse events No imbalance of non-ocular adverse events overall, except APTC arterial thromboembolic events only in. mg dose * : 3 subjects (2.%).3 ranibizumab: 3 subjects (2.2%). ranibizumab: 6 subjects (4.3%) Results consistent with previous ranibizumab trials Conclusions: 2 Month Vision Outcomes Clinically & statistically significant benefit vs in predominantly classic CNV ~9% lost fewer than letters letter improvement in mean VA 36-4% improved or more letters 6-2% improved 3 or more letters *Not powered to distinguish differences in rates of rare events among treatment arms Lucentis Activity Day : 2/2 Day 4: 2/63 (+7 letters) Bevacizumab RT=47 µ RT=66 µ RT = retinal thickness as measured by OCT. Courtesy of Dr. P. Rosenfeld, BPEI, Miami, FL. TMc 23-8 /6/2 :4:6 AM 3

14 What we do know What we do not know The Beginning: Systemic IST, Phil Rosenfeld, MD Case reported ASRS mtg - Montreal July 2 Within 6 months: THE STANDARD OF CARE Michels, Rosenfeld, Puliafito et al Ophthalmology, June 2 2(6):3-47 Open label, uncontrolled study 9 pts Systemic bevacizumab mg/kg Baseline and - 2 doses at 2 wk intervals Results: 6 wks: mild inc. BP; improved by 2 wks wk: improved VA 2 wks: median VA improved by 8 letters; OCT dec. by 9 µm Rosenfeld, Moshfeghi, Puliafito Ophthalmic Surgery, Lasers & Imaging Jul-Aug 2, 36(4):33- patient Responded poorly to pegaptanib (Macugen). mg wk: VA stable OCT resolution SRF, improved macular contour 4 wks: VA stable OCT maintained Avery, Pieramici, Rabena et al. Ophthalmology,March 26, 3(3): e 8 eyes/79 pts.2 mg q month until macular edema, SRF, or PED resolved wk: % reduction of > % of baseline retinal thickness OCT dec. central thickness by 6 µm 4 wks: 3/8 eyes complete resolution of macular edema, SRF, PEDs Mean VA improved from 2/2 to 2/2 OCT dec. central thickness by 92 µm 8 wks Median VA improved from 2/2 to 2/8 OCT dec. central thickness by 89 µm Costa, Jorge, Calucci et al. Investigative Ophthalmology and Visual Science,Oct. 26, 47(): pts, prospective, nonrandomized open label study.,., 2. mg BCVA improved at wk, wk 6, wk 2 79.% Stable or Dec. lesion area 74.4% Stable or Dec. CNV area Wk 2. mg: BCVA improvement by +.3 lines. mg: BCVA improvement by +.6 lines 2. mg: BCVA improvement by +. lines No systemic adverse events TMc 23-8 /6/2 :4:6 AM 4

15 What we do not know: Systemic Safety? Duration of clinical effects? Optimal dosing? Level Evidence: ABC Trial Presented by Tufail, Retina Congress October 29 vs Lucentis Comparison of AMD Treatment Trial > subjects enrolled at present (goal 2) Randomization: q month Lucentis q month variable Lucentis variable Enrollment expected to be completed by the end of 29 Primary outcome: Mean change in VA year results to be reported in 2 Lucentis or Other diseases Diabetic Retinopathy DME PDR CRVO CME NVI, NVG BRVO CME NVI, NVG Diabetic Retinopathy Proliferative Diabetic Retinopathy Avery et al. Ophthalmol 26;3():69-7.e- 44 eyes/32 pts regression of leakage on FA Complete resolution NVE 9%, NVD 73%, NVI 82% Recurrence of NV as early as 2 wks p Diabetic Retinopathy Proliferative Diabetic Retinopathy: small series Speeds resolution and dec extent of NV Jorge et al. Retina. 26;26:6-3 Tonello et al. Acta Ophthalmol 28;86: Mirshahi et al. Eur J Ophthalmol 28;8: Speeds resolution of VH Spaide et al. Retina 26;26: Moradian et al. Graefes Arch Clin Exp Ophthalmol 28;246:699-7 Dec intraop heme during PPVx as adjunct rx Ishikawa et al. Eye 29;23:8- Chen et al. Retina 26;26:699-7 Rizzo et al.graefes Arch Clin Exp Ophthalmol 28;246: Diabetic Retinopathy Diabetic Macular Edema Arevalo et al. Ophthalmology 27;4: eyes/63 pts, retrospective review f/u 6-9 months, 72% had injection % gain or more lines??? Mean 387 to 276µ TMc 23-8 /6/2 :4:6 AM

16 Diabetic Retinopathy Lucentis Diabetic Macular Edema: Lucentis Nguyen et al. Am J Ophthalmol 26;42: Nonrandomized trial pts,. mg at baseline,,2,4,6 months CFT 3µ to 27µ at 7 months VA improvement 2/8 to 2/4 Diabetic Retinopathy Lucentis Diabetic Macular Edema: Lucentis READ 2 Study: Nguyen et al. Ophthalmology 29 Randomized clinical trial, 26 pts, ::.mg baseline, months,3, Focal laser baseline and month 3 Focal laser + lucentis baseline and month 3 Month 6: gain BCVA 7.24 letters; -.43 letters; +3.8 letters Excess foveal thickness reduced by: %, 33%, 4% Diabetic Retinopathy Lucentis Diabetic Macular Edema: RESOLVE Study Randomized phase II trial pts w/ 3µ CMT Group A: 42 pts analyzed at 6 months Groups B: 9 pts analyzed at 2 months.3mg vs.mg vs sham: injections q month x 3 Treat to resolution; could double dose if DME present 7% pts double-dose; mean injections Group B: VA gain 7.6 letters vs.2 letters at 2 mo s Group A/B: Mean.3 letter gain vs -.4 letters CMT decreased from baseline -2µ vs -µ Retina Vein Occlusions Macular Edema: Wu, Arevalo, Roca et al., RETINA 28:22-29;28 4 eyes, BRVO, ME (mean dx 26 mo s, mean f/u 3 wks).2 mg, 24 eyes,. lines inc BCVA; µ at 6 mo s,. injections 2. mg, 2 eyes, 4.8 lines inc BCVA;38 24µ at 6 mo s, 2 injections Chung, Hong, Lee, Graefes Arch Clin Exp Ophthalmol : eyes, BRVO, ME, retrospective review 28 eyes letters gain, 3 eyes 2 inj 22 eyes < letters gain or worse VA 4 eyes 2 inj Retina Vein Occlusions Macular Edema: Hoeh, Ach, Schaal et al. Graefes Arch Clin Exp Ophthalmol.29;online; 6 pts (CRVO 27 pts; BRVO 34 pts) mean f/u 6 wks±29 wks (min 2 wks) CRVO: 748±26µ to 372±224µ, gain VA.9±3.2 lines BRVO: 6±26µ to 386±78µ 33% CRVO, % BRVO: no ME 2 wks 37% CRVO, % BRVO: ME recurrent within last 2 wks 3% CRVO, 3% BRVO: ME no complete resolution x 3 injections TMc 23-8 /6/2 :4:6 AM 6

17 Objectives Comparison of AMD Treatments Trials (CATT): Lucentis Trial Abdhish R. Bhavsar, MD for the Comparison of AMD Treatments Trials (CATT) Research Group Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS To determine the relative efficacy and safety of intravitreal Lucentis and for treatment of neovascular AMD To determine if less than monthly dosing of either drug compromises long term visual outcomes CATT Clinical Sites 28 patients with neovascular AMD enrolled at 44 sites in the United States Major Eligibility Criteria Goal was to be as inclusive and simple as possible Neovascular AMD with either choroidal neovascularization (CNV) or its sequelae (fluid, blood, PED) subfoveal Visual acuity (VA) 2/2-2/32 drusen (>63μ) in either eye or late AMD in fellow eye Fibrosis < % of lesion; no limit on hemorrhage No previous treatment for CNV in study eye Age yrs 99 CATT Treatment Treatment in PRN Arms Lucentis Monthly Monthly Lucentis PRN PRN 3 patients per arm (N=2) Month OCT-guided retreatment } Inject monthly unless dry Primary Endpoint Final visit Treat to a dry OCT zero tolerance for intraretinal, subretinal, or sub-rpe fluid. May also treat if there is other evidence of CNV activity New subretinal or intraretinal hemorrhage Leakage or increased lesion size on FA Unexplained decrease in visual acuity with no obvious atrophy or subretinal fibrosis. No retinal thickness threshold ( microns) as used in many neovascular AMD treatment studies. 2 TMc 23-8 /6/2 :4:6 AM 7

18 CATT Study Drugs (Lucentis ). mg (. ml) dose Locally supplied; same as for patients outside of the study Billed to primary and supplemental insurance providers Residual co-pay paid by NIH No out of pocket expense for drug CATT Study Drugs Bevacizumab ( ).2 mg (. ml) dose 2 cc vial containing.2 cc, IND #,476 Compounded by an aseptic fill and finish company (Formatech) 3 4 Masking Masked to drug and schedule Visual acuity examiner OCT and photograph graders Masked to drug Ophthalmologist Patient initially, billing statements may unmask Outcome Measures Primary Mean change in VA at year (non-inferiority limit of letters) Secondary Maintenance of vision (< letters lost) 3-line gain in VA ( letters on ETDRS chart) Change in fluid on OCT Change in lesion size on fluorescein angiography Number of treatments Incidence of endophthalmitis, retinal detachment, cataract, uveitis Incidence of systemic serious adverse events Cost 6 Patients 28 patients with neovascular AMD Enrolled at 44 clinical sites in US February 28 to December 29 (2. months) DSMC recommended exclusion of all patients (23) at one site due to protocol non-compliance All results reported on 8 patients Baseline Characteristics Mean age for Lucentis was 78.8 versus 79.7 for Groups were balanced for gender, race, baseline visual acuity, lesion type, and central foveal involvement by CNV. More patients assigned to had HTN, diabetes, were current smokers, had emphysema, had a history of MI, TIA, or arrhythmias. 7 8 TMc 23-8 /6/2 :4:6 AM 8

19 Masking 22,38 patient visits during the first year Drug identity known to treating ophthalmologist at only 46 visits (.2%) Two patients accounted for half (23) of the these instances Robust masking also in place for VA Examiners and Reading Center graders Visual Acuity Results 9 Mean Change in Visual Acuity Lucentis Monthly and Monthly Mean Change in Visual Acuity Lucentis PRN and PRN Lucentis Monthly Monthly 99.2% CI: (-3.9, 2.9) Lucentis PRN PRN 99.2% CI: (-4., 2.4) Letters Letters Week Week Mean Change in Visual Acuity Lucentis Monthly and Lucentis PRN Mean Change in Visual Acuity Monthly and PRN Lucentis Monthly Lucentis PRN 99.2% CI: (-4.7,.3) Monthly PRN 99.2% CI: (-.7,.6) Letters +8. Letters Week Week TMc 23-8 /6/2 :4:6 AM 9

20 Mean Change in Visual Acuity Lucentis Monthly and PRN Mean Change in Visual Acuity Monthly and Lucentis PRN Lucentis Monthly PRN 99.2% CI: (-.9,.8) Monthly Lucentis PRN 99.2% CI: (-4., 2.) Letters Letters Week Week Mean Change in Visual Acuity All Groups Change in Visual Acuity- GEE Model All Groups Averaged over Weeks 2,24, 36, 2 Letters Lucentis Monthly Monthly Lucentis PRN PRN Letters Lucentis Monthly Monthly Lucentis PRN PRN 7.2 (.7) 7.3 (.8) 6.4 (.6) 6. (.7) Week Week % CI for Mean Change in VA at Year All Groups Patients Without Letter Decrease Lucentis Monthly (n=284) Monthly (n=26) Lucentis PRN (n=28) PRN (n=27) % 93.7% 93.2% 94.% 9.6% 9% 8% Percentage of Patients 7% 6% % 4% 3% 2% % % 9 2 TMc 23-8 /6/2 :4:6 AM 2

21 -Letter Change from Baseline at Year -Letter Change from Baseline Over Time 2 22 Distribution of Visual Acuity Conclusions Visual Acuity at One Year Lucentis and were equivalent at all time points when administered at the same dosing regimen The proportion of patients with 3 line gain, < letter loss, or 2/4 or better was the same when either drug was administered with the same dosing regimen. Lucentis PRN was equivalent to Lucentis monthly (-.7 letters) PRN was equivalent to monthly through 36 weeks but was inconclusive at 2 weeks for visual acuity (-2. letters) Summary New ERA of more effective anti-vegf agents Lucentis Future Randomized clinical trials: Level Evidence DRCR Laser--Triamcinolone trials DRCR Protocol N, VH anti-vegf vs control inj More effective anti-vegf agents Combination therapies Sustained release vehicles Less frequent dosing regimens Better prevention strategies TMc 23-8 /6/2 :4:6 AM 2

22 Thank You! Additional Slides % of Subjects Primary Endpoint: Subjects Losing < Letters from Baseline at Month % *P <. vs. P <. vs. 94.%* 94.6%*.3 mg MARINA. mg (n=24) % of Subjects % (n=43) 94.3% 96.4%.3 mg (n=4) ANCHOR. mg (n=39) Secondary Endpoint: Mean Change in Visual Acuity Over Time ETDRS letters * P <. vs. Control mg (n=24) -..3 mg MARINA Note: Vertical bars are ± one standard error of the mean * letter benefit 7. * letter benefit mg (n=39).3 mg (n=4) Verteporf in (n=43) ANCHOR * letter benefit 8. * letter benefit Presumed Endophthalmitis Culture Positive Culture Negative Culture Not Done Key Ocular Serious Adverse Events (n=236 ) Uveitis Rheg. Retinal Detachment Retinal Tear MARINA.3 mg (.4%) 2 (.8%) One case reported as uveitis by investigator Same subject had 2 episodes each reported as uveitis, received systemic antibiotics once Vitreous Same subject Hemorrhage had 2 episodes.. mg (n=239) 2 (.8%) (n=43) ANCHOR.3 mg (n=37). mg (n=4) (.7%) (.7%) (.4%) (.7%) (.7%) (.7%) (.4%) (.4%) (.4%) (.4%) (.7%) (n=236) Vascular Death Nonfatal Myocardial (.4%) Infarction Nonfatal (.4%) Ischemic Stroke Nonfatal Hemorr. Stroke APTC * ATEs MARINA.3 mg (.4%) (.4%) (.4%). mg (n=239) (n=43) (.4%) (.7%) (.4%) (.7%) 3 (.3%) (.7%) 3 Total 2 (.8%) (2.%) 3 (2.%) (.3%) *Antiplatelet Trialists Collaboration. BMJ. 994 Jan 8;38(692):8-6 ANCHOR.3 mg (n=37) (.7%) (.7%) (.7%). mg (n=4) 2 (.4%) 3 (2.%) (.7%) 3 (2.2%) 6 (4.3%) TMc 23-8 /6/2 :4:6 AM 22

23 APTC * ATEs Pooled MARINA and ANCHOR Control (n=379).3 mg (n=37). mg (n=379) Vascular Death (.3%) 2 (.%) 3 (.8%) Nonfatal Myocardial Infarction 2 (.%) 2 (.%) 4 (.%) Nonfatal Ischemic Stroke 2 (.%) 2 (.%) 4 (.%) Nonfatal Hemorrhagic Stroke Total (.3%) 6 (.6%) (2.9%) *Antiplatelet Trialists Collaboration. BMJ. 994 Jan 8;38(692):8-6 TMc 23-8 /6/2 :4:6 AM 23