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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`125387Orig1s000
`STATISTICAL REVIEW(S)
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`Exhibit 2098
`Page 01 of 46
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` U.S. Department of Health and Human Services
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`- Office of Translational Sciences
`Office of Biostatistics
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`STATISTICAL REVIEW AND EVALUATION
`CLINICAL STUDIES
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`NDA/BLA Serial
`Number:
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`Drug Name:
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`Indication(s):
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`Applicant:
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`Date(s):
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`Review Priority:
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`125,387/SN-0000
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`Aflibercept ophthalmic solution (VEGFTrap-Eye)
`Treatment ofneovascular (wet) age-related macular degeneration
`(AMD)
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`Regeneron Pharmaceuticals, Inc.
`Submitted: February 17, 2011
`PDUFADate: August 20, 2011
`Priority
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`Biometrics Division:
`Statistical Reviewer:
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`Concurring Reviewers:
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`IV
`Dongliang Zhuang, PhD
`Yan Wang, PhD; Mohammad Huque, PhD
`Anti-inifectives/Ophthalmology
`Sonal Wadhwa,MD; WilliamBoyd,
`MikePuglisi
`Project Manager:
`Keywords: Neovascular(wet)sgerelsedmaculardegeneration(AMD),bestcorrected
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`NMD;WileyChambers, MD
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`Medical Division:
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`Clinical Team:
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`visual acuity (BCVA)
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`Exhibit 2098
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`Page 02 of 46
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`Exhibit 2098
`Page 02 of 46
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`ementsrenttNrene
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`LIST OF TABLESseonnmonrrninenennennanannnnnananannseuamntecsinsuanenmnesmenerasinseninemmene 3
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`LISTOFFIGURESsecesanessersesessdina4
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`EXECUTIVE SUMMARYocccoessecssssssssesersscotsssssinsesotnseseapsotsnessensssentestansessronencornisesnesensertvesesrmnesssessien 5
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`INTRODUCTION duvcovcncasedoceceeongsccscosescqvoscsesccanceoeavenooonesouessoecocspecse:00004Coeosescvrcnerececneseusosesetocerconececonerecueeeseoaesensers 7
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`2,1
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`Class and Indication .........sesssesssssssessssscsessarsssesssegusssosssssssessacssensssssseessesasesteaieesduossesasesesisansessoesetneenes 7
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`History ofDrug Development.........csssssesssossseissesescsssteegecsnenenesssesacesecsncesstacseasneeeseesorsesreteacecscsaneavacetes 7
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`Specific Studies Reviewed.....sssscsseessssssesrssasesssennensseenssersssenesneassseaeeneeseecaeranees“eapesvseseesoracennsenseees 10
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`DATASOURCES ..ascessessssssesssssssocssnsnseneenesnsssssussnsseneeeenesyosnososesoncencencnssanonan
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`3.2 EVALUATION OF EFFICACY.....ccssssosssesssssssossserecensvesenssessssssssessessessnnsasseosesenesees
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`Statistical Methodologies...sssssssseeiecsssserecessesssenaneseacseescenseecanes
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`Results and COnclUsions .......0ssecseecensevenenessavueteseenascenseensnses
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`EVALUATION OF SAFETY ........ececsssessserssosseorsseseuccenessneseaveneersvessensennesateenscoseosees
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`GENDER, RACE, AGE, AND GEOGRAPHIC REGION....,...ccssssssssesesssssessessrseansrearssssensersssesoneseonssaneeesaneas
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`OTHER SPECIAL/SUBGROUP POPULATIONS...eoverssssensensesJeaesersreneseacses
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`CONCLUSIONS AND RECOMMENDATIONS..............stsecsssevesessreneneasssssvsvseososotessesenesseseenecoseeosansessseaeosoesesoesees 40
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`APPENDICES...cossosssevsssoscssnesososhuccososstecseosonsasonssennscsonsnssscsossnnsscosssesausocosovsnscsccssonsnesecoonsnssnnercessuenssssssoenevavecensee 42 :
`SIGNATURES/DISTRIBUTIONLISTssnssnnssissennutnuusnnnenniuanemeneinnmnnrerivseeins 45
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`Exhibit 2098
`Page 03 of 46
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`Exhibit 2098
`Page 03 of 46
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`LIST OF TABLES
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`- Table 1: Keyefficacy results at week 52 - proportion ofsubjects who maintainedvision, change in BCVA score
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`from baseline, and proportion ofsubjects who gained >15letters in BCVA score from baseline (Full analysis set). 6
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`Table 2: Schedule of events (Year OMe)...:..ccsscssssseccssssssssesescsessssnssccssnscsonecessvecauscssnscesssessssecsecsessvecenseccssesersveraseeesseess 15
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`Table 3: Brief summary of Phase 3 studies...............-+.ssnssassetenssaressossuesouvesoceseperseseseoradvssersenenenesesstaveresseegeasuesouasseneacaes 17
`Table 4: Study VIEW 1 - Subject Disposition (Allrandomized subjects)......
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`Table 5: Study VIEW 2 - SubjectDisposition (All Randomized Subjects)..........s:csssserssessssesssserssersensseeseesees
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`Table 6: Study VIEW 1! - Demographics andbaseline characteristics (Full analysis SOCt) crececcssseroseonprssersensess
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`Table 7: Study VIEW2 - Demographicsandbaseline characteristics (Full analysis set) ..............sssssesevens
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`Table 8: Study VIEW 1 - Baseline disease characteristics in the study eye (Full analysis set)...............0:00
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`Table 9: Study VIEW 2 - Baseline Disease Characteristics in the Study Eye (Full Analysis Set) ..sserscessoeesavereapesones 24
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`Table 10: Number ofsubjects attending the study visits (Full analysis set) .............sssssssesccsssssssetsssssrensorerores
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`Table 11:.Proportion of Subjects who Maintained Vision at Week 52 (Per Protocol Set) ........c:csscsssssssssrseeseseseseeoses 27
`Table 12: Proportion ofsubjects whomaintained vision at week 52 (Full analysis SCt) c.ccscssssssscscsssscsescorsesersssossesue 28
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`Table 13: Reviewer's analysis ofproportionofsubjects who maintainedvisionatweek 52 [1]using CMHtest(Per
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`PTOCOCOI S€t).....esesscarsccrtscssseccesssessronessresonsesetsarorarsenessecsssossosasaesecscaonssorasnencecssnssetassesssessasasansosaessesessesecsensinsessceseenenseats 29
`Table 14: Reviewer’ss analysis ofproportion ofsubjects who maintained vision at week 52 [1] using CMH test (Full
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`AMNalySis SCt).......sersocscsssscessesersssecssencsessesenepensecsssesenssspconesseeiesarscosenesessecssssesssesseneonccssestonseecsstesseenserscacssesescesesensesesets 30
`Table 15: Reviewer's Analysis ofProportion ofSubjects who Maintained Vision at Week 52 (1) Using Multiple
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`Imputation (Per Protocol Set) .......scsccsssscossserscepseecesesssesscnsessessaccnesovasessusesesescorsesesaenesecnesscenccecseceseaqesenacanetecseasesseessaes31
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`_ Table 16: Reviewer’s Analysis ofProportion of‘Subjectswho Maintained Vision atWeek 52 [1]Using Multiple
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`Imputation (Full: Analysis Set)..:.............cscsssecchecsccscsrcssersceseeossnsosspnssesecesssnessneestassessssatseccsvecsnescsassasguassassesesenenceneeseens ‘32
`Table 17: Testing order ofsecondary efficacy variablesin pivotal studies (VIEW 1, VIEW 2).......scssecscssecsrseees33
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`Table 18: Change from baseline to week 52 in ETDRSletter score (LOCF) (Full analysis SCt)..sseescsersercseneeenersnsscens 35
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`Table19: Change from baseline.to week 52 in ETDRS letter score (multiple imputation)................scsessrssesesseesess 36
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`Table 20: Proportion ofsubjects who gained>15 lettersiin the ETDRSletterscore at Week 52 (LOCF)(Full
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`StalySis Set).......c...coresessssevesssscsssseseserserssssasasaesonssonsaesossssslesesenasassnssssesssnseseguecseatscsesenrecssesessscacasecseasscssassseesepssesseaceneones 37
`. Table21:Proportionofsubjectswhogained>15:lettersfintheETDRSletterscoreatweek 52(multipleimputation)
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`(Full analysis Set)... isscsesscssssesssoscsessocsesesecoscesssescosossssretsenensssesscscenesssecncensassesesaossevessesscenseussacusnessetesaracesoesseteqeesess
`Table A.1: Summary Statistics for ETDRS Letter Score, GibservedValues (VIEW 1; Full Analysis Set)................ 42
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`Table A.2: Summary Statistics for ETDRS Letter Score, Observed Values(VIEW 2; Full Analysis Set)..........00+ 43
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`Exhibit 2098
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`Page 04 of 46
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`Exhibit 2098
`Page 04 of 46
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`LIST OF FIGURES
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`Figure | : General flow chart for pivotal Phase-3 studies (VIEW 1, VIEW 2).:......ssssiscssssssesssesssessesesssseneissorssenerees 12
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`Figure 2: Proportion of subjects remaining in the study by visits (Full amalysis Set) .......:....scsecsossssessssssesssenssonerees 25
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`Figure 3: Mean change from baseline through week 52 in ETDRS letter score (LOCF) (Full analysis set).............. 34
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`Exhibit 2098
`Page 05 of 46
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`Exhibit 2098
`Page 05 of 46
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`1 EXECUTIVE SUMMARY
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`This BLA application seeks the approval ofVEGF Trap-Eye administeredintravitreally for the
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`treatment of neovascular (wet) age-related macular degeneration (AMD). The proposed dose for
`VEGF Trap-Eyeiis 2 mg administered by intravitreal injection once every 2 months, following 3
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`initial monthly injections of2 mg. VEGF Trap-Eye may be dosed asfrequently as 2 mg once per.
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`month.
`The efficacy ofVEGFTrap-Eyewas supported by clinical data from two Phase-3 studies,
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`VGFT-OD-0605 (VIEW 1)and 311523 (VIEW 2): Both studies were randomized, double
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`masked,active comparator (0.5 mg ranibizumab)controlled study. Subjectseligible for thestudy
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`were men and women > 50 years of age with active primary subfoveal choroidal
`neovascularization (CNV)lesions secondary to AMD.Foreach subject, one eye was designated
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`as the study eye. Atscreening, subjects had a best corrected visual acuity (BCVA)of20/40 to
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`20/320 (letterscore of 73 to 25) in the study eye; CNV in the study eyewere at least 50% oftotal
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`lesion size. Subjects were randomized to receive one ofthe four treatments: 2 mg VEGF Trap-
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`- Eye administered every 4 weeks, 0.5 mg VEGF Trap-Eye administeredevery 4 weeks, 2 mg
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`VEGFTrap-Eye administered every 8 weeks, and 0.5-mg ranibizumabadministered every 4
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`_ weeks. Subjects with all three subtypes of AMD (occult, minimally classic, and predominantly
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`classic) were allowed to enroll ineach VEGF Trap-Eye study. This reflected a synthesis ofthe
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`selection criteria of all pivotal trialsof the ranibizumab developmentprogram.
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`These twostudies demonstrated that VEGF Trap-Eyeis non-inferior to 0.5 mg ranibizumab with
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`_ respect to the proportion ofsubjects who maintained vision at week: 52, basedon a pre-
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`determined non-inferiority margin of 10%. The maintenanceofvision was defined as a loss,
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`relative to baseline,in visual acuity ofless than 15letters in the ETDRSletter score. In both
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`studies, nearly 94%of subjects treated with VEGF Trap-Eye and 0.5mg. ranibizumab maintained
`- vision at week52. Thefindings for 0.5 mg ranibizumab were similarto those fromthepivotal
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`ranibizumab studies used to support its registration. Furthermore, the design and conduct ofboth
`non-inferiority studies for theVEGF Trap-Eye program are consideredadequate.
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`Results from the analysis ofsecondary efficacy endpoints, including BCVA change from
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`baseline at week 52 and the proportion of subjects whogained atleast 15letters in the BCVA
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`score at week 52 compared with baseline,also supported the efficacy ofVEGF Trap-Eye —
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`comparedto 0.5 mg ranibizumab. Both VEGF Trap-Eye regimens and.0.5 mg ranibizumab were
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`associated with fairly similar change in BCVA score and proportion of subjects who gained at
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`least 15 letters in the BCVA score at week 52 compared with baseline. A summary of key -
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`efficacy results are presented in Table1.
`The analyses ofthe primary and secondary efficacy endpoints were conducted.according to pre-
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`specified statistical methodology. The Reviewer concurred with the pre-specifiedstatistical
`methodology and confirmed the primary efficacy and key secondary efficacy results for visual
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`acuity. Additional analyses employing different statistical approach or different method to handle
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`Exhibit 2098
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`Page 06of 46
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`Exhibit 2098
`Page 06 of 46
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`mnissing datawere performed bythe Reviewer. The results from these analyses were similarto
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`those presented in the submission.
`Table 1: Key efficacyresults at week 52 -proportionofsubjectswho maintained vision, change
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`in BCVA score from baseline, and proportion of subjects who gained = 15 letters in BCVA
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`- score from baseline (Fullanalysis set)
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`Number of
`Subjectswho
`.Mean(SD):
`Treatment
`Study
`'
`Gain of> 15
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`letters (%)
`subjects
`maintained .
`‘
`number of
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`vision (%)
`letters
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`VGFT-OD-_
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`0605 (VIEW 1)
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`311523
`(VIEW 2)
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`304
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`304
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`301
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`301
`291
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`93.8%
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`_—_—Ranibizumab
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`0.5Q4
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` 10.9(13.8)
`| VTE2Q4—.
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`6.9 (13.4)
`“VTE05Q4
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`7.9 (15.0)
`VTE 8Q4
`9.4(13.5)
`_Ranibizumab
`
`-
` 0,5Q4
`—
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`94.5%
`309
`29.4%
`VTE 2Q4
`7.6 (12.6)
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`98.3%
`-
`296
`34.8% .
`9714.1)
`VTE 0.54 :
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`VTE 8Q4 31.4% 306 95.4% 8.9(14.4)
`Note: Maintenance of‘vision was defined as a loss of<15 letters in the ETDRS letter score.
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`Source: VGFT-OD-0605 (VIEW 1) CSR Tables 20, 22, and 23; 311523 (VIEW 2) CSR Tables 21, 24, and 25.
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`95.1%
`95.0%
`94.4%
`94.8%
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`"
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` $.1(15.2)
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`30.9%
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`37.5%:
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`24.9%
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`30.6%
`—.
`34.0%
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`Therefore, the efficacy of VEGF Trap-Eye regimens was supported by a non-inferiority
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`_comparison to 0.5 mg ranibizumabfor the proportion of subjects who maintained visionat
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`week 52. Similarefficacy results observed with VEGF Trap-Eye and0.5 mgranibizumabin the
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`secondary visual acuity endpoints further substantiatedthe efficacy ofVEGF Trap-Eye -
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`compared to 0.5 mg ranibizumabfor treatment ofneovascular AMD.
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`
`Exhibit 2098
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`Page 07 of 46
`
`Exhibit 2098
`Page 07 of 46
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`

`

`2 INTRODUCTION
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`2.1 Overview
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`2.1.1 Class and Indication
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`VEGFTrap-Eye was developedfor the treatmentofneovascular (wet) age-related macular
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`- degeneration (AMD). The proposed dose for VEGFTrap-Eye is 2 mgadministered by
`intravitreal injection once every 2 months, following 3 initial monthly injections of2 mg. VEGF -
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`Trap-Eye may be dosed as frequently as 2 mg once per month.
`©
`AMDis the most common degenerative disease ofthe macula and is the most commoncause of
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`blindness in the developed world. There are two forms ofAMD,the dry and the wet form. The
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`dry form is more benigri and accounts for90% ofall AMDcases,but only for 10% ofcases of
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`blindness due toAMD.There is no treatment for dry AMD. Antioxidants and vitamins have .
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`been shown in certain subgroups to reduce the risk of AMD progression. Dry AMD may develop
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`into wet AMD,also known as neovascular or exudative AMD,whichis less prevalent. Wet
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`AMDaffects 10% of the AMD patients and is the more aggressive form. If untreated, wet AMD
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`leads to rapid severe visual impairment and legal blindness. About 80% to 90%ofpatients with
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`severe vision loss due to AMD have wet AMD,
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`Thetreatmentparadigms|forwet AMD shiftedtremendously when anti-VEGF treatment, notably
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`_Ranibizumab (Lucentis™; Genentech-Roche/Novartis), was introduced. Ranibizumab was
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`approved for the treatment of wetAMD inU.S.in 2006andsincethen,it has become the
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`standardof care in the treatment of wetAMD.
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`In the pivotal ranibizumab studies, monthly intravitreal administration ofranibizumab
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`maintained vision, defined as loss of <15letters, at 12 months in approximately 95% ofthe
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`patients. Additionally, ranibizumab resulted in gainof>15 letters in at least. 1/3 of patients in
`these studies. Clinical meaningful improvement was observediin mean visual acuity.
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`Intravitreal injection ofranibizumab poses potential serious tisk: and monthly regimenis
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`- burdensometo patients, caregivers, ophthalmologists and the healthcare system. VEGF Trap-Eye
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`is developed as an alternative treatment of wetAMD,whichisintended -to offer similar efficacy
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`as ranibizumab, but a more convenient dosing scheme. Accordingto theBLA submission, VEGF-
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`Trap binds to VEGF,with binding affinity higher than does the native VEGFreceptors.
`Moreover, unlikeother anti-VEGF molecules, VEGF Trapalso binds to PIGF, with higher
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`binding affinity than does its native receptor. The combination ofthese properties was expected
`to potentially contribute to longer lasting action, thereby leading to a dosing interval longer than
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`once monthly and, possibly, toimproved visual acuity as compared to standard therapies without
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`similar properties.
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`2.1.2 History ofDrug Development
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`_ Exhibit 2098
`Page 08of 46
`
`Exhibit 2098
`Page 08 of 46
`
`

`

`The development ofVEGFTrap-Eye for the treatment ofwet AMD was filed under IND 12462
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`on May 16, 2005 and opened on June 15, 2005.
`~ Theclinical development program for VEGF Trap-Eye in support ofthe proposed indication |
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`_ Started with two Phase-1 studies (VGFT-OD-0502 andVGFT-OD-0603) to assessthe safety of
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`single or repeated intravitreal injections ofVEGF Trap-Eye at doses between 0.05 and 4 mg.
`Phase-2 study VGFT-OD-0508 (completed on ine 26, 2008) was a double masked, prospective,.
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`randomizedstudy for the safety, tolerability andbiological effect ofrepeated intravitreal
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`administration ofVEGFtrap inpatients with neovascular age-related macular degeneration.
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`Approximately 150 eligiblepatients were randomly assigned with an equal chance toreceive
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`ITV injections ofVEGFTrapinto the study eye at 4- or 12-week intervals overa 12-week ©
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`. period. Treatment groups were as follows:
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`Group A: 0.5 mg VEGFTrap at 12-week intervals.
`Group B: 0.5 mg VEGF Trap at 4-week intervals
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`Group C: 2.0 mg VEGFTrap at 12-weekintervals
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`Group D: 2.0 mg VEGFTrap at 4-week intervals
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`_ Group E:4.0 mg VEGF Trap at 12-week intervals
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`Beginning at Week 16, subjects in alltreatmentarms were evaluated every 4 weeks for
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`subsequent PRN dosingat the randomized dose level for up to one year.
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`Visual acuity was assessed at Week 12. All treatment groups experienced improvements in
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`. visual acuity as early as Week 1, and these improvements were maintainedthrough Week12.
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`The VA improvement was maintained during Weeks 16through 52 (the PRN phase) with an
`average ofonlytwo additional doses during thistime.
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`. Subjects enrolled in Phase-1 or Phase-2 studies‘were allowed to continue treatment with VEGF.
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`Trap-Eye 2 mg PRN in an ongoing Phase-2 long-term safety study (VvGFT-OD-0702).
`- Two Phase-3 studies were conducted‘to generate the pivotal support forthe proposed indication.
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`The study protocol VGFT-OD-0605/14393 (VIEW 1) was first issued on January 15, 2007 and _
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`subsequently amendedthree times (Amendment 1 on May 24, 2007; Amendment 2on January
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`16, 2008; and Amendment3 on June 03, 2009).
`The Applicant submitted a Special Protocol Assessment (SPA) request for VGFT-OD-0605
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`(VIEW 1) on January. 18, 2007 (serial #060). The proposed design was a 2-year double-masked,
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`parallel, non-inferiority study of intravitreal VEGF Trap-Eye against ranibizumab for
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`maintenance of best-corrected visual acuity (BCVA)in patients with neovascular AMD.The.
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`proposed dose armsfor the first year were 4 mg every 4 weeks (4mgQ4), 1 mg every.4 weeks
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` (ImgQ4), and 4 mg every 12 weeks with shamdoses at interim monthly visits when VEGF
`Trap-Eyewas not administered (4mgQ12), or ranibizumab at 0.5 mg once everyfour weeks
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`(RQ4). In thesecond year, subjects \were to beevaluated every 4 weeks, and receive an
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`_
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`-
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`
`Exhibit 2098
`
`Page 09 of 46
`
`Exhibit 2098
`Page 09 of 46
`
`

`

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`intravitreal injection at least every 12 weeks. Injections could be given as frequently as every 4
`weeks, but no less frequently than every 12 weeks, accordingto specific criteria. The proposed
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`primary endpoint was the proportion ofsubjects who maintained vision. The maintenance of
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`vision was defined as loss ofless than 15 letters in best-corrected visual acuity on the Early
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`- Treatment Diabetic Retinopathy Study [ETDRS] chart compared to baseline at 12 months.
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`_ The proposed analysis was non-inferiority compared to ranibizumab, which was analyzed.
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`sequentially for each of the VEGF Trap-Eye dose groups in the following order: 4mgQ4,
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`followed by 1mgQ4, and then 4mgQ12. A confidence interval approach was plannedfor the non-
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`inferiority evaluation using a non-inferiority marginof 10%. Key aspectsofthe study design and
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`analysis plan were agreed upon by the Agency.
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`The Applicant submitted a second SPArequest (serial #074) on May 31, 2007 for Protocol
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`“‘VGFT-OD-0605 (VIEW 1). Changes were made to the VEGF Trap-Eye dose regimensto -
`include 2.0 mg VEGFTrap every 4weeks (2Q4), 0.5 mg VEGF Trapevery 4 weeks (0.5Q4) and
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`‘2.0 mg VEGFTrap every 8 weeks (2Q8)(with three consecutive doses at Day 1, Week 4 and
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`Week8),as well as ranibizumab0.5 mg every 4 weeks(RQ4). The proposed conditional
`sequencefor primary endpoint analysis was VEGF Trap 2mgQ4, 0.5mgQ4and then amgQs. In
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`addition, the primaryendpoint would be at week 52 rather thanweek 48.
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`The choice ofthe final dose groups in the Phase-3 program,i.e., 0.5Q4, 2Q4, and 2Q8, was
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`based on.the results ofStudy VGFT-OD-0508. Over thefirst 12 weeks, 100% ofpatients in the
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`2Q4 treatment group and 0.5Q4 treatment group maintained vision (defined as losing less than
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`15 letters on the ETDRSscale). In addition, the improvementsin visual acuity were similar in
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`the two 2 mg groups at Week 8, suggesting that an 8-week dosinginterval could:potentially
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`maintain the effects of VEGF Trap-Eye in Phase-3 studies. The time course of improvements
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`also suggested thatinitiating treatmentwith three monthly injections was associated. with a better
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`outcomethana single injection ofeither 2 mg or 0.5mg. In the PRN phase,a greater percentage.
`Ofpatients in the 2-mg group maintainedvision thanin the 0.5-mggroup, indicating that efficacy
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`ofthe 0.5-mg doseis moresensitive to dosinginterval than efficacy with the2-mg dose. Dosing
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`with 4 mg didnotresult in greater efficacy than dosing with 2 mg.
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`In response to the Agency’s comments as part ofthe SPAforthis protocol, theApplicant
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`. amended the protocol (Amendment 2). Amongthechanges,the statistical section was updated to
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`include treatment by site interaction analysesforall sites (including calculationsof confidence
`intervals for differences for all sites regardless ofsize).
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`Study 31 1523 (VIEW 2; VGFT.-OD-0618) followed essentially the same design as the VGFT-
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`OD-0605 (VIEW 1) study. The difference between the two studies is that Study VGFT-OD-0605
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`(VIEW 1) was conducted primarily in North America, and Study 311523 (VIEW 2) was
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`conducted primarily in Europe, Asia, Australia and LatinAmerica. At the time ofthe BLA
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`submission, the Phase-3 studiesare still ongoing.
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`The present applicationiis based on the data obtained through the end ofthe first year of
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`treatment ofthese two studies. The first year of the studies includes a direct comparison ofa .
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`Exhibit 2098 -
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`Exhibit 2098
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`fixed dosing every two months versus the comparatortreatment ranibizumab which is given at
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`monthly dosing. One year of treatment was expected to provide clinically relevant information
`onthe efficacy and safetyofthe respective treatment group. After completion ofthe primary.
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`endpoints,the studies continue for another year. Year 2 wasdesigned to evaluate the impact of
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`further prolongeddosingintervals andcriteria-based flexible dosing on the maintenanceofthe
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`visual acuity and morphological benefits achievedin the firstyear.
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`A pre-BLA meeting was-held on September 8, 2010 to discuss clinical issues concerning the
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`planned BLA submission.It was agreed that the key analyses for the summary ofclinical
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`efficacy would be derived from the1-year analysis of each individual Phase 3 studies(VIEW.1
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`and VIEW2), the pooled analysis ofthe 1-year data from the two Phase 3 studies and the Phase
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`2 study VGFT-OD-0508.It was also agreed that, for eachindividual phase 3 study, subgroup
`analysis for efficacy would be performed for the primary (loss of <15 letters) and secondary
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`visual acuity (mean change and 3-line gainers) endpoints. Sensitivity analysis wouldbe provided
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`for primary and all secondary endpoints,
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`2.1.3 Specific Studies Reviewed
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`TwoPhase-3 studies, Study VGFT-OD-0605 (VIEW 1) and Study 311523 (VIEW 2), are
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`selected for full statistical review and evaluation.
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`‘Study VGFT-OD-0605 (VIEW 1) is a randomized, double masked, active controlled study ofthe
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`efficacy,safety, and tolerability of repeated dosesofintravitreal VEGF Trap insubjects with
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`neovascular age-related macular degeneration. Subjects eligible forthe study were.men and
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`women > 50 years of age with active primary subfoveal CNV lesions secondary to AMD,
`includingjuxtafoveallesions that affect the fovea, as evidenced by fluorescein angiography.
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`(FA). For each subject, only one eye was designated as the study eye andreceived randomized
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`treatment.
`The planned sample size was 1200, and the subjects were to be recruited at multi-centers in USA
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`and Canada. At the conclusionofthe study enrollment, a total of 1217 subjects from 154 sites
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`were randomized to one of4 dosing regimens:
`«2 mg VEGF Trap-Eye administered every 4 weeks (204; N=304),
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`* 0.5 mg VEGFTrap-Eye administeredevery 4 weeks (0.5Q4; N=304),
`» 2 mg VEGF Trap-Eye administered every 8 weeks (2Q8; N=303), and
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`¢ 0.5 mg ranibizumab administered every 4 weeks (RQ4; N=306).
`. Subjectsassigned to (2Q8) received the 2 mginjection every 4 weeks to week 8 (at day 1,
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`week 4, and week 8) and then a sham injection at interim 4-week visits (when study drug isnot
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`administered) during the first 52 weeksofthe study. No sham injection was given at Week 52.
`The study duration for each subject was scheduled to be 96 weeks. For the first 52 weeks.
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`(Year 1), subjects received an intravitreal or sham injection in the study eye every 4 weeks.
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`During the second year of study, subjects were evaluated every 4 weeks and received an _.
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`Exhibit 2098
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`Page 11 of 46
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`Exhibit 2098
`Page 11 of 46
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`intravitreal injection at least every 12 weeks. During this period, injections were given as
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`frequently as every 4 weeks; but no less frequently than every 12 weeks, according to pre-
`specified clinical criteria. Sham injections were not given during the second year ofthe study.
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`Subjects were evaluated every 4 weeks for safety and best corrected visual acuity(BCVA) using
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`the 4 meter Early Treatment Diabetic Retinopathy Study (ETDRS)protocol. Quality of Life
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`(QOL)was evaluated using the N