A._1_\,ID Update
`
`Page 1 of 2
`
`The "T reat and Extend" D
`
`.
`
`~n!i-Vascu la r Endothelia i°i::;,i~et men of I ntravitrea I
`
`actor Therapy for
`eovascular Age-Related M
`acular Denen
`.
`eratlon
`
`Michael Engelbert MD
`
`:::i
`
`t'-'.'-:-~,:,;.:,,.:,,·
`~"-:·
`~t~~~t~"'ilt~~i-:.\~~(cid:173)
`~- ·-.
`.
`:,;.-.::;:-~-~i\~,:-. ... ::
`
`-' ·•;,,~·~ ~ ~----~·~-~,:;,~~
`,. 11,
`
`::::::,~
`
`· :•iwe•i~<'
`
`-~~~-;:..-...-...-... ................................ ~
`
`· •>:•:\::;:;,\
`
`Ingrid U Scott, MD, MPH, Editor
`
`Professor of Ophthalrr1olo
`,.
`Public Health S .
`,gy "nd
`cIences
`o
`, enn date College o· M d: .
`' e IcIne
`·
`0
`
`PR!NT FRISENDLY VERSION
`
`FORWARD TO CD LLEAGUE
`
`NEWSLETTER ARCHIVE
`
`~· Bailey Freund, MD
`E.dwar'd S Hark
`"
`-
`.
`I
`Surg,
`ne .. s E.ye lnstitutP r
`.
`'
`. 'e:ons, New York NY
`.,, _,o umb1a Un;versity C ii
`V1t,:eous-Hetina--Mac~1 C - ,
`o. ege o, Physicians &
`.
`l:uEsther T. Mertz
`.,a onsu1tants of New York
`.
`l l11s work ,s supported ~e;;~ar'.t~~e,arch Center, New' :o~: YN~k, NY
`ac .. ,a I oundat1on, Inc..
`'
`'
`
`j
`
`y:;
`~ While
`monthly inIect1ons of lflt"
`,'.,
`i::=,
`endothelial growth fa"'o-
`'-~ , av1treal anti-vascular
`. . aed mawla, deoeoernl·oo P;py ''"'°"'''"'"
`~-·
`J!lit
`aqe rel t
`·
`v• r ( vcGF) t~1er
`f
`~
`fflF
`visual outcom"s su "."
`'
`A D) have produced
`ffl froqoeocy of office ;',;"'.' 10 prim'°"''"'·" the
`,.
`~ -,~·\• tremendous burd~n ~-1~L~ a.nd inieclions can place a
`~
`·
`sy t
`,,ac1ents and the h
`I
`ra d
`n~ om1zed, double-bl:nd
`- - s em Unfortunately, the
`..
`'
`, ea th care
`3
`;eg,meo, ''.'lded lofeilm ~:~:,m:\°"'rolled trial mvesllgatio:';'~ ,1,01, wh,Oh Is t,o ooly
`osII,g Pm1ents lfl the PIER;, c;,J comes compared to outco ~ess frequem doslflg
`series of three monthly ,n-~ /a, were examined and treated mvs repmted afte, mont•11y
`employed three 1n1t1~il rr;o;rt~i'?ns ~he open-label, non-i;nd~~u_a:e~y followlflg an in,itial
`
`on changes in visual ac~1ty f. in~ecdons but was followed by· .. , i~A i- rONTO study also
`
`evaluation 4 5 Tl1e PrONTO. ,"''.r11.,al f1nd1ngs and opt,cal coher:s neecled" dosin9 based
`dosing with fewer in1ect1ons: egI.men appeared to achieve v1;~ nee to;no~rnphy (OCT)
`OCTs Furt~1er111ore after ·h b_u, patients still required mor"hl al _resul.s s1m1!ar to mon1h'y
`" Y v1s1ts, examinations a
`a!lowed nu1d to re a'._.,
`, ' e irnt1al mandated ser·"s
`,
`
`om cams rngaidl~g ;':,;::~:~;ti lhe '°"" befo,,'tr,~:,<,~~i'~:t:~'°°'· lhls prolo;ol od
`
`. epeated rn1s1ng
`.. ong-term vision loss and th .
`d
`hemorrhages dunn9 p
`eno s wahout VEGF 1nh1bilion.s 7 8
`, e poss1b1lity of new
`
`consists of at leas' ti ~
`
`The '·Treat and Extend' d
`0sIna rea•me 1 .
`.
`a~·
`·
`"nieve optimal visual res , - --
`• --·
`, ' is a tailored ma,ntenanc
`u_1b _w1,h two add1t1onai goal 9
`. : regimen intended to
`. ,
`absence ot macula.1 hrve 1nit1a1 monthly 1n,ectio'1' b ts Like P1t:R and PrO~HO it
`··
`' -', u ow·~ s·· bl
`t
`, r emo•rha o
`'
`o receive regular Ill .. t. ,
`g,,, _and a dry OCT ha , b vv • ,a e visual acuity, an
`a'·hie . d
`ain enance lflJeMio •~
`ve een achie-,od
`.
`t'
`I
`,. v . ,ve with montnly dosing 'I, '"' "" at increasing in•erval~ ~•-
`, pa ients continue
`-
`.nee stab1l:ty
`s
`• • .e Ll'n in ·--x·
`·
`T ct·an
`'·'· 0
`1n·ect10
`'" vveeKs Visua1
`' · , '· ges are recorded a
`n regardless of the
`·
`J •
`to t11e next visit (and , ct/ presence or absence of d's~a-~ain and pat,ents receive ·an
`
`' ' -
`
`"cu1ly clinical finding,· ~n-d ;)(~ le patient is inst,ucted ,0 ~ t
`parameters It there :r: ~~~ed injection) is based o~ ~/;,.~ct1v~y. However, the i~terval
`
`e,gi;t weeks (henco tn; te; --~~nges the intervai to the ne~_,er-~vd chan9e in tne above
`reat and Extend") , ., .
`, 'v1s1t is extended to sever
`renewed d1sea, e ;ct' ·t m
`shortened .. In o:1~ 0'"1I:'Icyl', t11e interval for tt1e next src,o h':de·vlerd, if there is evidence ·of
`. ' or
`an exa111InatIon beyond, 8:9 ~· . c ice, we rareiy extend the . io c1on and examina11on IS
`,,. ' 1nical nm t'
`d
`·
`v 1J e
`irre 't'
`weeks.
`in ,,r-,al between injections
`
`" ...
`One goal of "Treat and Ext
`patient visits and the nu~b:nd '." to reduce the treatment bu
`monthly visits necessitat~d t~ o: I111agI;1g studies perform~d brd:,n by r,educing number of
`lfl ac~1ieving this g , I .
`y
`lterna.ive dosing s1rate , . y
`,im1na.1ng t~1e need for 'I
`· ·
`g,es. We r~ce1Jt'
`· ',e
`. oa In two sma'I
`-
`·
`and type 3 (retinal an .
`,,
`' ' co_:orts of eyes with newl
`.' v , --.
`,y reported success
`1
`eyes wit~1 type 3 vess~ll~~"dous prol1reration}11 neovasc I·
`; diagnosed type 1 (occult}'o
`a a sustained visual impro u.ar,zat1on. In these reports th
`, vement of appro .
`.
`, , e
`ximately 2 Snellen
`
`http://wv,1v1 "1·s1·c)n~ -
`ess10naLcomtem ·1 /
`' m s amdupdate/index asp"°
`cmenrofi
`·
`· · nssue'"42
`i-
`' · v
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`
`1/24/2018
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 655
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`

`

`A._1_\,ID Update
`
`Page 2 of 2
`
`lines while the eyes with type 1 vessels achieved visual stabilization. The number of office
`visits and injections was reduced by 25-50% compared to a monthiy dos;ng regimen.
`
`A second goal of the "Treat and Extend" dosing regimen is to reduce the risk of new
`sight-threatening submacular hemorrhages. We recentiy demonstrated a statistically
`significant increase in macular hemorrhages when patients in the PiER trial were
`switched from a monthly to quarterly dosing regimen 6 Unfortunately, large and potent;al!y
`devastating submacular hemorrhages may occur almost immediateiy after a high-quaiity
`8 Theoret;cally, eyes treated with an
`OCT examination showing an absence of tluid. 7
`·
`OCT-guided "as needed" regimen, in which patients may go iong intervais without VEGF
`suppression, couid tie at a greater risk for sigt1t-threatening submacular hemorrhages
`compared to eyes receiving more frequent and reguiar anti-VEGF treatments. In our two
`retrospective series, we did not obse1ve any sight-threatening macular hemorr~1ages.
`Aiso, uniike tt1e ANCHOR, MARINA and PrONTO studies wt1ich are iimited to 24 months
`of foliow-up, 17 of our 28 patients completed 36 month follow-up. We are not aware of
`any ot~1er dosing regimen of anti-VEGF therapy that ~1as demonstrated stable or improved
`VA out to tt1ree years.
`
`While initial results of the "Treat and Extend" dosing regimen appear promising, the
`strate9y requires further validation in a larger randomized t1iai. Ciinicians should view the
`current data regarding different regimens criticaliy when deciding whicll dosing strategy is
`best for individuai patients.
`
`REFERENCES
`
`1. Rosent'eicl PJ, Bmwn DM, Heier JS, et al. Rc:1nib:zu!T1ab for neovasculc:11 age-related macuiar de-generation. N Engl J Mee!
`2006: 355: 1419-31
`2. Brawn DM, Kaiser PM, Michels M, e1 al. Ranihizumab versus verteporforin for r.eovascuiar age-related macuiar
`degeneration N Engei ,J Med 2005; ~155: i4~:S2-i444
`.:-. Reg!i!o CD, Brown DM. ,\branarn P. et aL R.andom!zed, double-masked. sham-controlled tria! of ra,1:b:zunK1b for
`neovascular age-related macular degeneration· Pi ER Siudy year 1. Am J Ophthalmol. Feb 2008;145(2):239-248.
`Fung AE, Latwar.i GA, Rosenfeld PJ. et aL An optical coherence tomography.guided, variable dosing regin1en with
`:11trav!trea1 ranibizumab (Lucentis) t'or neovascu!ar age• rc-lc:1ted marnlar degeneration. Am J Oµhtna:moi. Apr 200?;14~:I
`(4):566-583
`5. Lalwani GA Rosenfeld PJ, Fung AE et al. A variable-dosing regimen with iniravttreai ranibizumab for neovascular age(cid:173)
`related nmculc:11 degc-nc-raticn: year 2 of the PrONTO Study. Arn J Opl]tha!rnoi 2009 Ju1;140(!).43-58.e1. Epub 2009 Apr
`18.
`6 Barbazeito i, Saroj N, Freund KB. Dosing regimer. and the frequer.cy of macuiar hemorrhages ir. neovascular age-reiaied
`rnacuiar degeneration treated with ranibiz.ur,iab. Poesented at the Annual Meeting of the Retina Society, September 2008
`Margolis R. Freund KB. Hemo!!IK1g:c recurrence of neovasculc:11 age-related macuiar de-generation not pred:cted by
`spectral domair. optical coherence tomography. Retinal Cases and Brief Reports, in press.
`i_evine .JP, Marcus I, Sorenson .JA, r:>paide RF, Cooney M.J, Freund KB. Macuiar l1emorrhage in r,eovascuiar age.related
`,11acu1ar clegencratio!l after stab:lizat!cn w:111 antiangicgenic therapy. Rc-tma. 200!..~ Sep:29t8):1074··9
`Spaide R. Rar.ibizumab according 1o need: a treatment for age-related macular degenera!icn. Am J Oplltha!rno:. 2007
`Apr:14~1(4):679-80.
`iO. E.ngelbert M, Zweifel SA, F1eu11cl KB. Lo11g-term Foi!cw-uµ fer Type 1 (sub•RPE} Neovasculc:1rizat!cn usi11g a ''Treat and
`Extend" Dos:ng Regimen of lnlrav:!reai Ant:-vascu!ar Endothelial Growth Factor Therapy" Retina, accepted for publ:cation.
`1 ·1. Er.gelbert M, Zweifel SA, Freund KS "Treat and e:,.iend'' dosing of intravitreal ar.tivascular endoiheiial grm,vih factor
`therapy for type 3 rieovascul3riz.atior,/retinal ar,giornatous proliferation. Retina 2009 Nov-Dec:29(10):1424·~11.
`
`8.
`
`Erratum
`
`We apologize that !ast month's article, Comparison of Two Doses of /ntravitrea/
`Bevacizumab as P11mary Treatment for Su/Jfovea! CNV Associated wit/J AMO at 24
`Months: The Pan-American Coi/aborative Retina Study Group by J. Fernando Arevalo,
`MD. FACS and IVlartin A Serrano, IVID was Of'iginally scheduled fof' a later issue but
`was in error released in May 2010.
`
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`http://www. visioncareprofessionai .com/emai I s/amdupdate/index.asp?issue"A2
`
`1/24/2018
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 656
`
`

`

`BLA 125387 /S056/S-058
`Page 5
`
`HIGHLIGHTS m' PRESCRIBING INl<'OllL4'.TION
`These highlights do ilOt iilclude all the foformatioil needed to use KVLli~A
`safely and effe1.'tively. See full prescribing information for EYLEA.
`
`EYLEA" (aflibercept) liljectioil, for Intravitreal Injection
`Initial U.S. Approval: 2011
`
`-------RECENT JVIAJOR CHANGES------(cid:173)
`Dosage and Ad.'Tlinistra1ion (2)
`8/2018
`Warnings and Precautions, Thromboembolic Events (':i '3)
`8/2018
`
`--------lNlllCATIONS MW USAGli~ - - - - - - - (cid:173)
`EYLEA is a vascular endothelial growth factor (VEGF) inhibitor irrtlicated for
`the treatment of patients with:
`Neovascular (Wet) Age-Related Macular De generation (Al'v!D) ( L l)
`•
`• Macular Edema Following Retinal Vein Occlusion (RVO) (L2)
`Diabetic Nfacular Eden1a (DNfE) (-! 'J)
`Diabetic Retinopathy (DR) in Patients withDME (l,4)
`
`------DOSAGli~ AND ADMINISTRATION------
`• Neova,cular (\Vet) Age-Related Macuiar Degeneration (AJ\'lD)
`• The recornrnendftl dose for EYLEA is 2 mg (0,05 mL) administeffd by
`intravitreal injection every 4 weeks (approximately every 28 days.
`morrthiy) for the first 3 mcm!hs, followed by 2 mg (0,05 mL) via
`intravitreal injection once every 8 weeks (2 months), (2.2)
`• Although E YLEA may bf dosed as frfqufntly as 2 mg every 4 weeks
`(approximately every 25 days, monthly). additional efficacy was not
`demonstrated in most patients when EYLEA was dosed every 4 wefks
`compared to every 8 weeks, Some patients may need every 4 week
`(mon11'Jy) dosing after the first l2 weeks (3 months)_ (2,2)
`Althou.gh not as effectlVe as the recommended every 8 week dosing
`regimen, patients may also be treated with one dose every 12 weeks after
`one year of effective lherapy, Patients should be assessed regularly,
`
`• Macular Edema Following Retinal Vein Occlusioil (RVO)
`• The recommended dose for EYLEA is 2 mg (0,05 mL) adrnimstered by
`in1ravitreai irJectiorr once every 4 weeks (approximately every 25 days.
`monthly), (2,3)
`
`li'lli.l. PRl!:SCRIHING INl<'ORM.ATION: CONTl<'.NTS*
`
`1NIHCAT10NS ANH USAG.!i'.
`l. l
`Necya:;cuL:r (\Vet) /-\g%-~R%J:n%-d Jvtacular Di:gi:necnjca u~-.J\iD)
`I\{JndarEdt:ma F'clk>-,,:l!3g Rt:tirn~J V~-:in Oc•,.Jnsion (RVO)
`l.2
`D:~:bet~c rvta:..~i_:Jar Ed?::.11a {DfvtE-J
`J .3
`J .4 DiahttiG Reti11opafrry ~DR) i1lPatlelltS. ~Nlth Dl\'1E
`UOSAG.!i'. AND AlHHNlSTRATlON
`lmportant fr:jection IrEtn;ctions
`2.l
`Nee,,ascuJa1 (\'/et) _Ag~-:~ll~-:lnk:d l'-.-1acu1ar Dfgfn1~1ntie::-1 (AJ\1fD)
`-r-.,tar.ul.0:: Ed.~1~_13 _FelkH-;1j:.1_g H~ti.nal V?:ln Ck~:..~lusi.on (R VO)
`?.3
`DiahttiG l\'1act:Jar Ederna {Dl\.fE)
`2.4
`.r.~;
`_:_;:_0be:j_:.,~ Ueti.nopathy (_:)R ! in I\~tjents tvjth_ D:\JE
`Pl\.:{>~:ratjon frn- Ad1n£nj:;tration
`2.f;
`!njfcfj_(Hl Proc1~du1t-:
`·• r
`llOSAGf; FORJHS ANH §TlffNGTHS
`CONTRAiNDKATlONS
`4. l
`Or.ul.0:: e: P?::::oc~d~~r l!.\fr;;:ctjn:.1_3
`,~\c1i,.,,-e Imrt:.oct:lar Ir:.::.:1amn1aiion
`-I.2
`
`WARNINGS Af'sD 1'm;CAlJT10NS
`E:xlaphthnhr:.dis ;::.::-1d R-..~tin;;:.l Dctach::-ricnts
`5. l
`lncrf;as~ ju lntraoct:Jar T-1H':3Surf;
`Thrornbot:mbolic Evtm:;
`AllVfll§E Rf.'.ACfWJ'sS
`Clin3 c~:! T r3 aj :; -Expe~·ii: nee
`6.J
`6,2
`lr::-1H1UDDJ!f:t1lcity
`
`2
`
`6
`
`• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in
`Patients with niabetic Macular li~denrn
`• The recommended dose for EYLEA is 2 mg (0,05 mL) adrnimstered by
`in1ravitreai irJectiorr every 4 weeks (approximately every 28 days,
`monthly) for lhe first 5 i~jectiorrs followed by 2 mg (0,05 rnL) via
`intravitreal injection once every 8 weeks (2 months), (},4. L~·)
`* Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(approximately every 25 days. monthly), additional efficacy was no1
`demonstrated in most patients when EYLEA was dosed every 4 weeks
`compared to every 8 weeks. Some patients may need every 4 week
`(monthly) dosing aftsc·r the first 20 weeks (5 months), (2A. 2 5)
`
`------DOSAGE FORMS AND STRENGTHS-----(cid:173)
`ln1ect1on: 2 mg/0JJ5 mL solution for intravitreal rnjection in a single-dose vial
`(3)
`---------<'ONTRAINDICATIONS--------
`• Ocular or periocnlar infection ( s-.J)
`• Active intraocular i11i1a..,11mation ('+,2)
`• Hypersensitivity ( 4, 3)
`
`------WARNINGS AND PRi!X~AllTIONS - - - - - -
`• Endophthalmitis and retinal detachments may occur following intravitreal
`ittjfctions, Patients should be instructed to report any symptoms suggfstive
`of endophthalmitis or retinal detachment without delay and should be
`managed appropriately. (5, l)
`lncreases in intraocular pressure have been seen within 60 minutes of an
`intravitreal injec1ion_ (5,2)
`• There is a potential risk of arterial thromboembolic events following
`intravitreal use ofVEGF inhibitors. (~,3)
`
`•
`
`--------ADVF~RSE RF~ACTlONS - - - - - - - (cid:173)
`The most common adverse reactions (~5';,o) reported in patien1s receiving
`EYLEA were conjunctival hcmonhag1.\ eye pain. cataract vitreous
`detachment, vitreous floaters, and intraocular pressure increased. (6, l)
`
`To report SUSPl''.CTlrn ADVERSJI REACTIONS, contact Regeuerou at
`1-855-395-3248 or FDA at 1-800-FDA-1088 or tt'Hw,fda.govlmedwatch.
`
`See 17 for PA TIE NT COUNSELING INFORMATION.
`Revised: 08/2018
`
`·Pregnancy
`H.J
`L.actation
`8,2
`Females and :\,[:;,ts of Reprndi.:.cti,e Poknlial
`i'U
`Pedlatdc lJ St:
`8A
`Gerjatric Us~
`R.~
`Di!:§CR.l.PTlON
`CUNJCAI. PHARMACOI.OGY
`12.; Mcchar,t;;m of /\cl.ion
`12.2 P};.:un1ac•xlyr:.atr:.:.cs
`J 2.3 r1hnn1uK:okinet:cs
`NONCUNKAI. TOXlCOLOGY
`13.1
`c~~rd:.102-enes~s. ·r-.,tutag;;;:n;;;:sjs_ hnpairrr~~r~l of F~Th!jty
`LLl Aai1nal Toxicology .:md/o~· ·pJwrrnacolog3,(cid:173)
`CUN1CAL STUDrnS
`J\:e0vascuJ:3r (\?./i:t _i Age'"r-Lelated l\.'J;Ki]hr Deger:_erati0n (A_r·vrJ) _i
`J 4. _t
`f-..·iacult:.r Ede1l1t:_ 1-:;·otiG'.:vi:ng Cer:tral Retlnat \/ti11 Occil1:;l(~!3
`J 4.2
`(CU\/0)
`I\{Jndar Edt: ma F'clk>-,,:l!3g Br;n1cb Rt:£inn1 Veir:_ Occlusim1
`(BRVO}
`J 4.4 Di~:hi:tk f\-laccJar Ederna H)f\-lE)
`14.5 Dj_abC;:'llc Rt'tj_n(1pathy (DR) ir:_ Patit'rHs ~.,,ith DA-tE
`HOW SUPl'Uf.:1)/STORAGi'. AJ'sD HA:'>/HUNG
`PATffNT COUNSEUNG lN1IORJ\V·,TWN
`
`1 :L J
`
`*Sections or subsections omitted from the full prescrihiug iilformatioil
`are not listed
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 657
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`

`

`BLA 125387 /S056/S-058
`Page 6
`
`:FULL PRESCRIBING INFORl\1ATION
`
`1
`
`INDICATIONS AND USAGE
`
`EYLEA is indicated for the treatment of:
`
`1.1
`
`1.2
`
`1.3
`
`1.4
`
`2
`
`2.1
`
`Neovascular (\Vet) Age-Related l\!lacufar Degeneration (Al\!ID)
`
`:M:acular Edema Following Retinal Vein Occlusion (RVO)
`
`Diabetic lVIacular Edema (Dl\!lE)
`
`Diabetic Retinopathy (DR) in Patients with DJVIE
`
`DOSAGE AND ADl\HNISTRATION
`
`Important Injection Instructions
`
`For ophthalmic intravitreai injection. EYLEA must only be administered by a qualified
`physician.
`
`A 5-micron sterile filter needle (19-gauge x l 112-inch), a 1-rnL Luer lock syringe and a 30-gauge
`,, ~0.-inch sterile injection needle are needed.
`
`EYLEA is available packaged as follows:
`
`• Vial Only
`
`• Vial Kit with Injection Components (filter needle, syringe, injection needle)
`I [see Hmv Supplied (16)].
`
`Neovascular (\Vet) Age-Related l\Iacufar Degeneration (Al\U))
`2.2
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreai injection every 4 weeks (approximately every 28 days, monthly) for the first
`12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(approximately every 25 days, monthly), additional efficacy was not demonstrated in most
`patients when E'YLEA was dosed every 4 weeks compared to every 8 weeks
`[see Clinical Studies (1-f. l)]. Some patients may need every 4 week (monthly) dosing after the
`first l2 weeks (3 months). Although not as effective as the recommended every 8 week dosing
`regimen, patients may al so be treated with one dose every 12 weeks after one year of effective
`therapy. Patients should be assessed regularly.
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 658
`
`

`

`BLA 125387 /S056/S-058
`Page 7
`
`l\ilacular Edema Following Retinal Vein Occlusion (RVO)
`2.3
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection once every 4 weeks (approximately every 25 days, monthly) [see
`C!iuica! Studies (! 4. 2), (! 43)].
`
`Diabetic l\'Iacular Edema (DivIE)
`2.4
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(approximately every 25 days, monthly), additional efficacy was not demonstrated in most
`patients when EYLEA was dosed every 4 \veeks compared to every 8 weeks [see C!iuica!
`Studies (f 4. -!)]. Some patients may need every 4 week (monthly) dosing after the first 20 weeks
`(5 months).
`
`Diabetic Retinopathy (DR) in Patients with Dl\ilE
`2.5
`The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by
`intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first
`5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks
`(2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks
`(approximately every 25 days, monthly), additional efficacy ,vas not demonstrated in most
`patients when E'YLEA was dosed every 4 weeks compared to every 8 weeks [see C!iuica!
`Studies (l 4.5)]. Some patients may need every 4 week (monthly) dosing afrer the first 20 weeks
`(5 months).
`
`Preparation for Administration
`2.6
`E'YLEA should be inspected visually prior to administration. If particulates, cloudiness, or
`discoloration are visible, the vial must not be used.
`
`The glass vial is for single use only.
`
`EYLEA is available packaged as follows:
`
`• Vial Only
`
`• Vial Kit with Injection Components (filter needle, syringe, injection needle)
`
`[ see Ho,i.· Supplied (I 6)].
`
`Use aseptic technique to carry out the following preparation steps:
`
`Prepare for intravitreal injection with the following medical devices for single use:
`•
`a 5-micron sterile filter needle (19-gauge x l ~'2-inch)
`•
`a 1-mL sterile Luer lock syringe (with marking to measure 0.05 mL)
`•
`a sterile injection needle (30-gauge x 112-inch)
`
`l Remove the protective plastic cap from the vial (see Figure I)
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
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`

`BLA 125387 /S056/S-058
`Page 8
`
`Figure l:
`
`2. Clean the top of the vial with an alcohol wipe (see Figure 2).
`
`Figure 2:
`
`3 Remove the 19-gauge x l 112-inch, 5-micron, filter needle and the 1-rnL syringe from their
`packaging. Attach the filter needle to the syringe by t\visting it onto the Luer lock syringe tip
`(see Figure 3).
`
`Figure 3:
`
`4. Push the filter needle into the center of the vial stopper until the needle is completely inserted
`into the vial and the tip touches the bottom or bottom edge of the vial
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
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`

`BLA 125387 /S056/S-058
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`
`5. Using aseptic technique withdraw all of the EYLEA vial contents into the syringe, keeping
`the vial in an upright position, slightly inclined to ease complete withdrawal. To deter the
`introduction of air, ensure the bevel of the filter needle is submerged into the liquid. Continue
`to tilt the vial during 'vvithdrnvval keeping the bevel of the filter needle submerged in the
`liquid (see Figures 4a and 4b ).
`
`Figure 4a:
`
`Figure 4b:
`------.'\
`'\
`
`'
`
`/
`
`\
`
`l
`
`--\
`
`""'"·'·....,,_- Needle Bevei
`,
`Pointing Down
`
`\
`
`Solution
`
`6. Ensure that the plunger rod is drawn sufficiently back when emptying the vial in order to
`completely empty the filter needle.
`
`7. Remove the filter needle from the syringe and properly dispose of the filter needle.
`Note: Filter needle is not to be used for intravitreal injection.
`
`8. Remove the 30-gauge x \0.-inch injection needle from its packaging and attach the injection
`needle to the syringe by fim1ly twisting the injection needle onto the Luer lock syringe tip
`(see Figure 5).
`
`Figure 5:
`
`q
`
`\Vhen ready to administer EYLEA, remove the plastic needle shield from the needle.
`
`10. Holding the syringe with the needle pointing up, check the syringe for bubbles. If there are
`bubbles, gently tap the syringe with your finger until the bubbles rise to the top
`(see Figure 6).
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
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`

`BLA 125387 /S056/S-058
`Page IO
`
`Figure 6:
`
`11. To eliminate all of the bubbles and to expel excess drug, SLO\VL Y depress the plunger so
`that the plunger tip aligns with the line that marks 0.05 rnL on the syringe
`(see Figures 7a and 7b).
`
`Figure 7a:
`
`Figure 7b:
`
`;,,:::tfa:t:::::~:·<1
`
`...
`
`Solution after
`expelling air bubbles
`and excess drug
`
`Flat Plunger
`Edge
`
`Injection Procedure
`2. 7
`The intravitreal injection procedure should be carried out under controlled aseptic conditions,
`which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a
`sterile eyelid speculum ( or equivalent). Adequate anesthesia and a topical broad---spectrum
`microbicide should be given prior to the injection.
`
`Immediately following the intravitreal injection, patients should be rnonitored for elevation in
`intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic
`nerve head or tonometry. If required, a sterile paracentesis needle should be available.
`
`Following intravitreal injection, patients should be instructed to report any symptoms suggestive
`of endophthalmitis or retinal detachment ( e.g., eye pain, redness of the eye, photophobia,
`blurring of vision) without delay [see Patient Counseling information (J 7)].
`
`Each vial should only be used for the treatment of a single eye. If the contralateral eye requires
`treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 662
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`

`BLA 125387 /S056/S-058
`Page 11
`
`speculum, filter, and injection needles should be changed before EYLEA is administered to the
`other eye.
`
`After injection, any unused product must be discarded.
`
`DOSAGE FORl\!IS AND STRENGTHS
`3
`Injection: 2 mg/0.05 mL clear, colorless to pale yellow solution in a single-dose, glass vial for
`intravitreal injection.
`
`4
`
`CONTRAINDICATIONS
`
`Ocular or Periocular Infections
`4.1
`E'YLEA is contraindicated in patients with ocular or periocular infections.
`
`Active Intraocular Inflammation
`4.2
`E'YLEA is contraindicated in patients with active intraocular inflammation.
`
`Hypersensitivity
`4.3
`EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the
`excipients in EYLEA. Hypersensitivity reactions rnay manifest as rash, pruritus, urticaria, severe
`anaphylactic/anaphylactoid reactions, or severe intraocular inflammation.
`
`5
`
`\VARNINGS AND PRECAUTIONS
`
`Endophthahnitis and Retinal Detachments
`5.1
`Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis
`and retinal detadunents [see Adverse Reactlons (ti.!)] Proper aseptic injection technique must
`always be used when administering EYLEA. Patients should be instructed to report any
`symptoms suggestive of endophthalmitis or retinal detachment without delay and should be
`managed appropriately [see Dosage and Administration (2. 7) and
`_f) ct tie n! (~crutrse l i11g ll{,ffJr1ru1t1t>.n (17)].
`
`Increase in lntraocular Pressure
`5.2
`Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection,
`including with EYLEA [see Adverse Reactions (6. !)]. Sustained increases in intraocular pressure
`have aiso been reported after repeated intravitreai dosing with vascular endothelial growth factor
`(VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be
`monitored and managed appropriately [see Do.§ag:e and Administration (2. 7)]
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 663
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`

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`
`Thromboembolic Events
`5.3
`There is a potential risk of arterial thromboemboiic events (ATEs) following intravitreal use of
`VEGF inhibitors, including E\7LEA. ATEs are defined as nonfatal stroke, nonfatal myocardial
`infarction, or vascular death (including deaths of unknown cause). The incidence ofreported
`thromboembolic events in ,vet Al'v1D studies during the first year was 1 .8%; (32 out of 1824) in
`the combined group of patients treated with EYLEA compared \vith 1.5<;,o (9 out of 595) in
`patients treated with ranibizumab; through 96 weeks, the incidence was 3.3% (60 out of 1824) in
`the EYLEA group compared with 3.2% (19 out of 595) in the ranibizumab group. The incidence
`in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of
`patients treated with EYLEA compared with 2.8~o (8 out of 287) in the control group; from
`baseline to week 100, the incidence was 6.4~'°o (37 out of 578) in the combined group of patients
`treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no
`reported thromboembolic events in the patients treated with EYLEA in the first six months of the
`RVO studies.
`
`ADVERSE REACTIONS
`6
`The following potentially serious adverse reactions are described elsewhere in the labeling:
`
`• Hypersensitivity [see Contraindications (t3)]
`
`• Endophthalmitis and retinal detachments [see iVamings and Precautions (5.1)]
`
`•
`
`Increase in intra ocular pressure [see JiVarnings aud Precautions (5. 2)]
`
`• Thromboembolic events [see rvornings and Precautions (5.3)]
`
`Clinical Trials Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials
`of the same or another drug and may not reflect the rates observed in practice.
`
`A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3
`studies. Among those, 2110 patients were treated with the reconunended dose of 2 mg. Serious
`adverse reactions related to the injection procedure have occurred in <0.1 % of intravitreal
`injections with E\7LEA including endophthalmitis and retinal detachment. The most common
`adverse reactions (?:5(;;o) reported in patients receiving EYLEA were conjunctiva] hemmThage,
`eye pain, cataract, vitreous detachment, vitreous floaters, and intraocular pressure increased.
`
`Neovascular (\Vet) Age-Related I\,facular Degeneration (Al'vID)
`
`The data described below reflect exposure to EYLEA in 1824 patients with wet A.1\,ID, including
`1223 patients treated with the 2-mg dose, in 2 double-masked, controlled clinical studies
`(VIEWl and VIEW2) for 24 months (with active control in year 1) [see C'!iuica! Studies 04.l)].
`
`Safety data observed in the EYLEA group in a 52-week, double-masked, Phase 2 study were
`consistent with these results.
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
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`

`BLA 125387 /S056/S-058
`Page l3
`
`Table 1:
`
`Most Common Adverse Reactions (:2:1 °A,) in \Vet AMD Studies
`
`Adverse Reactions
`
`Baseline to Week 52
`
`Baseline to Week 96
`
`Conjunctival hemorrhage
`
`Eye pain
`
`Cataract
`
`Vitreous detachment
`
`Vitreous floaters
`
`Intraocular pressure increased
`
`Ocular hyperemia
`
`Corneal epithelium defect
`
`Detachment of the retinal pigment
`epithelium
`
`Injection site pain
`
`Foreign body sensation in eyes
`
`Lacrimation increased
`
`Vision blurred
`
`lntraocular infiammation
`
`Retinal pigment epithelium tear
`
`Injection site hemorrhage
`
`Eyelid edema
`
`Corneal edema
`
`EYLEA
`(N=1824)
`
`25%
`90; /0
`
`7°/o
`
`6%,
`
`6%
`
`5%
`
`4%
`
`4%
`
`101
`_, /0
`
`3%
`
`3%
`
`3%
`
`2%
`
`201
`,/0
`
`)Oi ~lo
`
`1%
`
`1%,
`
`1%,
`
`Active Control
`(ranibi:mmab)
`(N=595)
`
`28%
`
`9%
`70/ /0
`
`6%
`
`7%)
`
`7~/~;
`
`8%,
`
`5%,
`
`3%
`
`3%
`
`4%,
`
`1%,
`
`2%
`
`3%)
`
`1%
`20/ /0
`')0/ ~10
`l o.1 /0
`
`Retinal detachment
`
`<1%;
`
`<1%
`
`EYLEA
`(N=1824)
`
`Control
`(ranibizumab)
`(N=595)
`
`27%
`
`10%
`
`13(1/o
`
`8~~J
`
`8%
`70; /0
`
`5%
`
`5%
`
`,...(,,'
`:, 1/o
`
`.... ()/
`j /0
`
`4%
`
`4%
`
`4%,
`
`3%
`
`2%
`
`2%
`
`2%
`
`1%
`101 /0
`
`30%
`
`10%
`
`10%
`
`8%
`
`10%
`
`11%
`
`10%
`
`6'1/o
`
`5%~
`
`4%
`
`4%
`
`2%
`
`3%~
`
`4%,
`
`2%
`201 /0
`
`3~~
`l oi /0
`
`1%;
`
`Less common serious adverse reactions reported in < 1 ~o of the patients treated with EYLEA
`were hypersensitivity, retinal tear, and endophthalmitis.
`
`Reference ID: 4308227
`
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2008 PAGE 665
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`

`

`BLA 125387 /S056/S-058
`Page 14
`
`Macular Edema Following Retinal Vein Occlusion (RVO)
`
`The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in
`218 patients followfog CRVO in 2 clinical studies (COPERNICUS and GALILEO) and
`91 patients following BRVO in one clinical study (VIBRANT) [see Clinical Studies U-t2),
`(l-1.3)].
`
`Table 2:
`
`Most Common Adverse Reactions (:::::1 % ) in RVO Studies
`
`Adverse Reactions
`
`CRVO
`
`BRVO
`
`Eye pain
`
`Conjunctiva! hemorrhage
`
`Intraocular pressure increased
`
`Corneal epithelium defect
`
`Vitreous floaters
`
`Ocular hyperemia
`
`Foreign body sensation in eyes
`
`Vitreous detachment
`
`Lacrimation increased
`
`injection site pain
`
`Vision blurred
`
`Intraocular inflammation
`
`Cataract
`
`Eyelid edema
`
`EYLEA
`(N=2l8)
`]3%~
`
`lX%
`
`Control
`(N=142)
`5%
`
`1lt>{,
`
`8%
`
`5%,
`
`5%
`
`5%
`
`3%)
`"0/
`
`.) /0
`
`".'10/
`_, /o
`
`''."01
`_, /o
`
`1%)
`
`1%)
`
`<1%
`
`<1%
`
`60/ /0
`
`4%
`
`1%
`
`·10-'
`_, lo
`
`5t1{,
`
`4%
`
`4%
`
`1%
`
`<1%
`
`1%
`10/ /0
`
`1%
`
`EYLEA
`(N=91)
`4%
`
`2O%i
`-,o,
`.., 1/o
`
`2'1/~
`
`l %~
`
`2%~
`
`3%i
`
`2%
`
`3~,~
`l o1 /0
`
`1%;
`
`0%;
`50'
`- 1/o
`
`1%
`
`Control
`(N=92)
`,o-'
`_, lo
`
`4t1{,
`oo;;)
`
`0%
`
`0%
`
`2%
`
`0%
`
`O%i
`
`0%
`
`0%
`
`l t1{,
`
`(/'{,
`
`0%
`
`0%
`
`Less common adverse reactions reported in <l % of the patients treated with EYLEA in the
`CR VO studies ,vere corneal edema, retinal tear, hypersensitivity, and endophthalmitis.
`
`Diabetic JVfacular Edema (DJVIE)
`
`The data described below reflect exposure to E\7LEA in 578 patients with DME treated with the
`2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to
`week 52 and from baseline to week 100 [see Clinical Studi