CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`BLA APPLICATION NUMBER:
`125156
`
`MEDICAL REVIEW
`
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`

`

`Medical Officer’s Review #3 — Labeling and Postmarketing Commitment
`
`_ Application Type
`Submission Number
`
`BLA
`125156
`
`Primary Reviewer
`
`Rhea Lloyd, M.D.
`
`Date of Labeling Submission
`Date of Postmarketing Commitment
`Submission
`Date of Labeling Review
`
`June 28, 2006
`
`June 29, 2006
`June 29, 2006
`
`Name
`
`Applicant
`
`Lucentis (ranibizumabinjection)
`
`Genentech, Inc.
`1 DNA Way
`South San Francisco, CA 94080
`650-225-1558
`
`Submitted
`The applicant has submitted labeling based on previous review, internal discussions and
`correspondence between the applicant and the Office of Antimicrobial Products with
`revisions to Section 12.2.
`In the second sentence of paragraph 2, the word “months” was
`
`capitalized. In the last sentence ofparagraph 2, the phrase, C
`was replaced by “Fovealretinal thickness data.”
`
`Also submitted, as agreed during the 29 June 2006 teleconference between the Agency
`and the applicant, are the following additiona] Postmarketing Commitments:
`
`1. Submit the final Clinical Study Report from Study FVF3689g by 30 June 2008.
`
`2. Provide safety and efficacy data from a 2-year adequate and well-controlled
`clinicaltrial ofa mutually acceptable design exploring multiple dosing
`frequencies of Lucentis. The timelines are outlined below:
`
`Protocol Submission:
`Study Start:
`Final Clinical Study Report:
`
`14 November 2008
`2] September 2009
`1 April 2013
`
`Reviewer’s Comment:
`Acceptable.
`
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`

`

`‘|
`
`Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`YY
`
`§ 552(b)(4) Draft Labeling
`
`§ 552(b)(5) Deliberative Process
`
`Withheld TrackNumber:Metical
`
`|
`
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`

`

`Recommendations
`It is recommended that BLA 125156 be approved with the labeling contained in this
`review.
`
`The application supports the safety and effectiveness of Lucentis (ranibizumab injection)
`for the treatment of — — a neovascular£& — J age related macular degeneration.
`
`Has Co
`
`ce:
`
`L->
`fj
`William Boyd, MD ‘7 Oana, .
`Wiley Chambers, MDS" & Peyae
`Janice Soreth, MD
`Mark Goldberger, MD, MPH
`
`APOTEX V. REGENERON IPR2022-01524
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`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumabinjection)
`
`Page | of 41
`
`Deputy Division Director Review
`
`Application Type
`Submission Number
`
`Established Name
`Trademark
`
`Therapeutic Class
`
`Applicant
`
`BLA
`125156
`
`Ranibizumab injection
`Lucentis
`
`Vascular endothelial growth factor
`(VEGF)inhibitor
`
`Genentech, Inc.
`1 DNA Way
`South San Francisco, CA 94080
`650-225-1558
`
`Proposed Dosing Regimen
`Lucentis is to be administered as an intravitreal injection 0.5 mg (0.05 mL) every oneto three
`months.
`
`Indication
`Treatment of © —
`
`3 neovascularc — 3 age related macular degeneration
`
`Intended Population
`Adults with neovascular (wet) age-related macular degeneration
`
`Formulation_
`
`us
`
`~ histidine HCl
`C —
`
` |
`
`
`
`lo, a-trefslosedehydrate|i
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 005
`
`Polysorbate 20
`| Water for Injection
`J
`—_
`* Targetfill volume of #m™m pervial.
`
`IIL
`
`APOTEX V. REGENERON IPR2022-01524
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`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 2 of 41
`
`Table of Contents
`
`DEPUTYDIVISION DIRECTOR REVIEW .......::::sssesssesesessssesseseneesereneseacsenesceneseseensenenensenseeasseneeasseneneataneseseneeess 1
`
`EXECUTIVE SUMMARY...ccccsssssssereesneetenenesseasssssseseessssesssnsasscnececescsuanssesesescsusessaensasecescsnsnsessasecesenscssagesssanacecssseases 4
`
`RECOMMENDATION ON REGULATORY ACTION ........2.00:ccec:ceesseeeseecsceeceecsaeeeessesaeseaeeepeguaeeeseeasesseeeseceeaaecesueeseeeeeeesenuee 4
`RECOMMENDATION ON POSTMARKETING ACTIONS .......ccccccssecsesseeessseeecseacesaeseneeseeeseueeeeeesscesseaceesaueesenreeseecneceersueeses 4
`Risk Management ACtiVity.....c..ccccsessesecssssseeesecsesesscsessssesesscseensecessnssessnesessssavaseesosssseeesscaesrsisecssenegesteneseseaeeesenaeets 4
`Required Phase 4 Commitments .............:ccccescssssessceeessceescecsersssecesescatseesssucsassassssnaeaeseneessseeesssenssasscsestereeeeraseeeey 4
`Other Phase 4 Requests .0............cccecccceceeseecesseccesesceececcecesnnsssceeseescessensecssessseeegeaesepeaenecesssssessessensastetegeesseceeretees 4
`SUMMARY ...cccsececeeccececeeesesseuaeessceesescesesueuaunusuceesescanaureeneersesscersseeeeesrserersstesectrepagesssssecseeseseeeessenaeeeccsegaesepegersserssreeners 4
`EffCACY oo. eeeesecesecesseececteeseessseecsesesesesssesacssevavscseserseseaneseeauscgsessssssacasssuenaverananassceasaseesesseesseresenssessnesssasseessasasseseners 5
`Safety o..ecceccccecscccsesssesessescscsccnssssssescsssesssnsusucsssessscssaneneseasasueaesescsesuaneneneaeseseeeseaesesesenessesseseausesessenensaeeeaesenensscneaee® 5
`Dosing Regimen and Administration.................+jecteceaneenntnosssaetavssuesssasauatocgussunesncsuesaassnessncastenectecnatovenscstetcess 5
`Drug-DrugInteractions ........cccsessecesesessesrssesscenssesssussucusasenssnsussscessesvenssecisasassssecnsaeacessusnessssusaseesaessanensasasavanensess 5
`Special Populations.............ccseccceseseseseeecsesesessseseesscansneseccenssenteeseseeaeseneseaessanescanecsutanssusvanesatsusessensessessaeseesasecaenss 5
`
`INTRODUCTION AND BACKGROUND. 1....ccsscseesessensntssesceseneneresseersenserncessenerreneeesfeowssesnecesvececstoonsessnecccesessseseseses 6
`
`PRODUCT INFORMATION .0...ccccccesceeesseesensceeeeererscesseesssscenscescenesegenecscesseaseseesecseeaesgeeeaseaesaeesesseseeeiseacaeenscauegeasonsges 6
`CURRENTLY AVAILABLE TREATMENTFOR INDICATIONS......cccccecescseceesessenesesseeeescaesaraceensceceneseeseneeseaeserseeacsesareesaenens 6
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES......2cscseereeeeeenes
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES........
`
`CMC (AND PRODUCT MICROBIOLOGY,IF APPLICABLE) .......ccccccescsesscsesesceeescsceeeseteesesseneeaeenaeseenanerscaeeeseesecsesenaesenaees 6
`ANIMAL PHARMACOLOGY/TOXICOLOGY....c...c000ccc0ecescsteceseceseeencneeseseererseeeecsececeuaeeeecsageeeeeeaeeesauseeesseeneneeecnaeseneneeens 7
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY......cccccssecseeseseesseesercenseesesencenseseecsanseneeneens 8
`
`SOURCES OF CLINICAL DATA....... vevccecscscenacecguusssusuecscsueseessenereeeecstsccsesecsueecesaceanacenseeceqsteqeeaeeeceeaeqesegeenseeenaeaeeeeeseees 8
`TABLES OF CLINICAL STUDIES .....0..c0c0c2ccccececce cep cececesesseesaceescesecvarcsasstseeaeseaeseeeseasenaeeeseauaerasenecees
`
`REVIEW STRATEGY...cccccceccsceescccceeceessenecsceceecsuaecsseseeessseeceeseeacauseeussceuaeesueuaseesueeseneeaseeeeuersesresee®
`DATA QUALITY AND INTEGRITY....c.cccesssscsescseersecsssesesconseacssserescserescssscecaeseneesessecastansessegeeeeneeeesenenes
`ve
`COMPLIANCEWITH GOOD CLINICAL PRACTICES.........ccccccsceeseesseeeenceeeseceeeeaaeceaareuseanetenenee’leeceseseee
`FINANCIAL DISCLOSURES........c.cc00c0c0eeeccseeeeeseeste cesses ceuseceussseneceascsccesseenseerseeesseeesecessccessceeseseqeeerseeeaeceeaeecereeensens 10
`
`
`
`CLINICAL PHARMACOLOGY .0....cccsccscssesscencssncsesecsseosescnansueenqsecsecssassasensucagensasceus sausceerensrseneeseesneencansenssenserseees 10
`
`.....0.0c000.cc-cocceeeeescescessescuseeseenaccsaneaecaaaeeeguveeeseececsseeasecneeeecsaaeeeeseeeeaee 10
`PHARMACOKINETICS — SEE PRIMARY REVIEWS,
`PHARMACODYNAMICS = SEE PRIMARY REVIEWS. 00000000
`cc coccece eevee cece ccceteeeeeenesceueaueceeeeuseserseeseeaseeeceseceeeseceenneeesceaeeees 10
`EXPOSURE-RESPONSE RELATIONSHIPS «0.0000 cccccc0
`csccsceee ceseseceseseesscoeesecevsesessnseessseaeeaeearsesseesesneeeereraetecseaeeersseaeeeeee LO
`
`INTEGRATED REVIEW OF EFFICACY....ccccsccsscerssenccssneressenesscsssusecaseneusesennansseneeeteereeereaneseqecasseqeeassaseneenneensenes 11
`
`Efficacy Conclusions.............:06c: 00 cesses cece eespeveveneusesserecsvsvavevinasssinsasasaeseasseeascaseceesseeeneevanaerseesecsaseesess 18
`INTEGRATED REVIEW OF SAFETY vnccccssccosseccscoressecessessesccspeccessencescscenascssenscseseessnenessaqseeeseneceanseenarsnenseaneanseeess 19
`
`Reported Adverse Event.......c:.:ccscccssssessesccesesesserecestiseseceesneenerecscsnnensasnessesasacnsaeesanecerevesecssensaeessaesensnenseeseetaneys 19
`Human Carcinogenicity.......-..c.cccccssccseeecssecsesesesesseeeeresennensseecssessssavsuayeressenacesasecavevavensuegersesseetsseeeesnenenenceesences 24
`Withdrawal Phenomena and/or Abuse Potential ........00.....00ccccco ccc ceeeeneeeesenneseugaeeeeneceusaeaeseesnacesaseeteneeaesserererses 25
`Human Reproduction and Pregnancy Data... oo eccceccceeeccsesseseseseceeneeeeneneeeeneaeseseeneaeeessennenenseraneetenseseaeageys 25
`
`-
`Assessment of Effect on Growth.
`co
`ca seanaenescavaceusvaesssseesassarerseageraseateesratanerseassarss 25
`Overdose Experience.......0.005..0.0 606.00
`Soe S cecneceees
`Gusts
`Postmarketing Experience...
`.
`;
`ce beets
`oseceeeeaees coceeeceeereceuse sescecsersanecsesseeqeeatesesasaeseee 25
`
`ADDITIONAL CLINICAL ISSUES .isccccccconcssoerresrsserseenenenaseneecesensstersngussacgorencoscessasecesosensaeqeaeseesecesaseanteceseeaceeeneeees 25
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 006
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`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 3 of 41
`
`DOSING REGIMEN AND ADMINISTRATION.......c-2::ccceccsseeessseeeesceseeeeseceeeeceesessccesueceeneeecaeeeceaeenaaeecaeeeeeeeeeeccaaeeeseeeaaees 25
`DRUG-DRUG INTERACTIONS ....ccccccscccseessceceecesseeeseceeseescseeessessuscnacesuuscuecegeensesssesseauessageesereeesenaeeesseseesteassnaeeecreneses 25
`SPECIAL POPULATIONS........ccsccsscessceessecseceaceescccecsceseeescessesueseassesneuseceeecegenenaesenaeseacseageeccaeenangeccaeeeeseeeaesaeeeseesensesee 25
`PEDIATRICS..cccccsscccssceecccscescescecsseseesscssesesutessesaesssensrssacessesuenscsasessessessesscesasessecsssenecsaceeacecssecaeeeesesaeeseeaeesaseecenseaeees 26
`
`ADVISORY COMMITTEE MEETING......
`LITERATURE REVIEW.....cccccccceccccseccessssceeseseesscsceecsceeessssaeseceenuesceeceeesnsceseenceaauaeaesceeeegueguessauaaeeaeccgeeeeecuaeeeseegecieaeaeees 26
`POSTMARKETING RISK MANAGEMENTPLAN.,....c.cccescccessseeseeesceoteessesstecseeeesaeeeeesseauessaueeeseesscaecstseeeeesseasenseseeetenaeees 26
`OTHER RELEVANTMATERIALS....c..cccccccceeeeeesseceeesecesesseeeescesuasceeeececeaaeeeceeessuaeseeeseeseeeeeaueaaeeeseseceeeeeecndeeeseneeeseeeeeees 26
`
`OVERALL ASSESSMENT......sssssssssssssssscsncossnsessnssncsncasansnseneascosanesssnssssonsosessesonsosessavsncssensnsanecssssessoessousessssssseosessoss 41
`CONCLUSIONS........ccccccccccceccceetecescecacecosessscencecesssceesceseesssaeeessenuecsnecesestacenecensueceueescaseseaeenaeeeseaeeesscgesecesegeseeeeneetiaees . 41
`RECOMMENDATION ON REGULATORY ACTION ..c..cccccccccccccscesceseeecesssessescesuesueesaccsaeesssentecseeeaseesecsseecuesaueeaesaeersestteees 41
`RECOMMENDATION ON POSTMARKETING ACTIONS ..........c::cecsceceeeceeeeeeseeneeeeceaeeeeeeeseeeeecesaeesseeseeeeeeerseeeeseeseseeseeees 41
`Risk Management Activity .........csscsccsccsesecessescsnscsseaveuersersneasanssssnersanenesessanauecessananesaneseneaesnsneneneseeneneneanesesneneaes 41
`Required Phase 4 Commitment............-.cccceccsccsscssesesseseereneensnesesneneentacaeensneneneausneeneneaeseaeetsaesetenneeensensneneeeeenes 41
`Other Phase 4 Requests .........c:c:ccccesceeeeseseeee ees ces
`ce ccecee seceee anetecsescenssneneneceneneeenes Error! Bookmark notdefined.
`
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`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`EXECUTIVE SUMMARY
`
`Page 4 of 41
`
`Recommendation on Regulatory Action
`Lucentis (ranibizumab injection) with the labeling changeslisted in this review is recommended
`for approvalfor the treatment of C ——1 neovascular
`— J age related macular
`degeneration.
`
`The applicant, Genentech Inc. has conducted three adequate and well-controlled studies,
`FVF2598g, FVF3192g, and FVF2587g which demonstratedstatistically and clinically significant
`differences in the proportion of subjects who lose fewer than 15 letters in best corrected vision at
`12 months compared with sham treatment.
`
`Recommendation on Postmarketing Actions
`Risk ManagementActivity
`Nopost marketing risk managementactivity beyond the usualcollection of adverse
`events is recommended.
`
`Required Phase 4 Commitments
`r
`
`~?
`
`L—
`
`,
`
`"3.
`
`Other Phase 4 Requests
`There are no other Phase 4 requests.
`
`Summary
`Established Name
`(Proposed) Trade Name
`Therapeutic Class
`Route of Administration
`
`ranibizumab injection
`.
`Lucentis 0.5 mg
`vascular endothelial growth factor (VEGF)inhibitor
`intravitreal injection
`
`the non-
`Age Related Macular Degeneration (AMD)is clinically manifest in twodistinct forms:
`exudative (dry) or the exudative (wet) form of the disease. The etiology of the disease is such
`that new abnormal blood vessels proliferate from the choriocapillaris through defects in the
`Bruch's membraneunderthe retinal pigment epithelium (RPE), forming neovascular membranes.
`These new vessels leak serous fluid and maygive rise to serous and hemorrhagic detachment of
`the RPE and neurosensoryretina and maystimulate fibrous disciform scarring with subsequent
`loss of central vision.
`
`Neovascular AMDis characterized by CNV in the macular region. Vascular endothelial growth
`factor-A (VEGF-A) has been observed in surgically excised human fibrovascularlesions.
`It is
`
`APOTEX V. REGENERON IPR2022-01524
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`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumabinjection)
`
`.
`
`Page 5 of 41
`
`reasonable to suggestthat active forms of VEGF-Aare targets for therapeutic intervention in
`neovascular AMD.
`
`Efficacy
`The three phase 3 studies submitted, Study FVF2598g, Study FVF2587g, and Study FVF3192g
`were designed to demonstrate the safety and efficacy of Lucentis (ranibizumabinjection) in the
`treatment of neovascular AMD. All three studies were prospective, multicenter, randomized,
`double-masked,parallel group. Study FVF2598g and FVF3192g had sham controls, and Study
`FVF2587¢ had an approved photodynasnic therapy as a control. All three studies demonstrated
`clinically andstatistically significant differences between ranibizumaband the control arm. The
`effectiveness of dosing every three months appeared to be onlyonethird as effective as monthly
`injections. Based on the population studied, there does not appear to be any difference in
`Lucentis’ effect based on age, race, ethnicity oriris color.
`
`Safety
`The population studied was predominantly elderly and white which is representative of the
`population usually affected by age-related macular degeneration. The demographicsof the
`patient population do not reflect problems with recruitment.
`
`The most common adverse events identified are conjunctival hemorrhage, eye pain, increased
`intraocular pressure, retinal disorder and vitreous floaters. These adverse events are often
`associated with intravitreal injections.
`
`_
`
`Dosing Regimen and Administration
`The sponsorhas performed adequate dose ranging and dose frequency studies of Lucentis
`(ranibizumabinjection). Lucentis has been proven safe and effective when administered as an
`intravitreal injection 0.5 mg/0.05 mL once monthly. This dosing regimen achieved and
`sustaineda statistically significant difference in the proportion of patients wholost 15 letters of
`vision comparedto baseline relative to the control group. When Lucentis is dosed every three
`months,it appears that 2/3 of the effectivenessis lost.
`
`Drug-DrugInteractions
`In Study FVF2587g, Lucentis (ranibizumab) was dosed with verteporfin PDT. Significant
`inflammation was observed when Lucentis was administered 7 days following PDT,but not
`when dosedat intervals longer than 7 days. No drug-drug interaction analyses were performed.
`
`Special Populations
`Subgroup analyses did not reveal any differences in the safety or efficacy with respectto age,
`sex, baseline visual acuity, CNV lesion type,lesion size, or prior laser photocoagulation. The
`population studied for this indication was predominantly elderly and white, reflective of the
`population mostaffected by this disease. The numberofpatients outside of this demographic
`group wastoo small to draw any definitive conclusion regarding the safety and efficacy. No
`pediatric trials were conducted for this drug as age-related macular degenerationis a disease seen
`only in adults.
`
`APOTEX V. REGENERON IPR2022-01524
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`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`,
`
`Page6 of41
`
`INTRODUCTION AND BACKGROUND
`
`Product Information
`
`ranibizumab injection
`Established Name
`_Lucentis 0.5 mg
`(Proposed) Trade Name
`vascular endothelial growth factor (VEGF)inhibitor
`Therapeutic Class
`Route of Administration—_intravitreal injection
`Chemical Class
`VEGFInhibitor
`Indication
`Treatment of neovascular (wet) age-related macular degeneration
`
`Currently Available Treatment for Indications
`There are currently two approved drug products for the treatment of age related macular
`degeneration — Visudyne (verteporfin for injection) and Macugen (pegaptanib sodium injection).
`Visudyne was approved under NDA 21-119 on Apri! 12, 2000, for the treatmentofpatients with
`predominantly classic subfoveal choroidal neovascularization due to age-related macular
`degeneration. Macugen was approved under NDA 21-756 on December 17, 2004, for the
`treatment of neovascular (wet) age-related macular degeneration.
`
`Availability of Proposed Active Ingredient in the United States
`Ranibizumabis a new molecular entity and has not been marketed in the United States.
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`CMC(and Product Microbiology, if Applicable)
`Formulation
`
`5
`
`
`
`Ph. Eur.
`USPand Ph.Eur.
`| NF and Ph. Eur.
`USP and Ph. Eur.|
`
`
`ference to
`
`
` Ingredients
`f
`
`
`
`Ranibizumab
`__| Active ingredient
`
`a, a-trehalose dehydrate
`| T : -
`_
`4
`— histidine HCl
`| c- 3
`
`Cc — 4
`!
`Polysorbate 20
`L—
`Injection _
`“* Targetfill volume o. ~~ pervial.
`
`|
`
`Genentechintendsto use a life-cycle approachfor setting ranibizumab specifications. This life-
`cycle approach will use interim acceptance criteria based upon the limited data available at the
`time of submission. Since campaign-to-campaign variation can be larger than the variation
`within a campaign, Genentech proposes a post-approval commitmentfor re-evaluating the
`
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`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumabinjection)
`
`Page 7 of 41
`
`- interim acceptancecriteria after three commercial post-approval campaigns (consisting of a
`minimum of — additional lots). The re-evaluation is expected to take place within two years
`after approval but will ultimately depend onthe currently unknown manufacturing schedule for
`ranibizumab Drug Substance.’
`
`Lucentis Drug Product Release and Shelf-Life Specifications.
`
`
`
`Tact Code|Test Name Acceptance Criteria Shelf-life
`
`
`
`[
`
`_
`
`|
`
`-
`
`Animal Pharmacology/Toxicology
`There were no significant findings in the pharmacology/toxicology reviews which wouldaffect
`the clinical outcome.
`
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`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 8 of 41
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY
`Sources of Clinical Data
`This review is based on the primary reviews from the Clinical, Pharmtox, Product Quality,
`Biopharm andStatistical staff and results of the applicant supported trials for AMD conducted
`under BBIND ——_ Three phase 3 safety and efficacy trials were submitted to support the
`indication currently being soughtby the applicant. In addition, the results of four phase 1/2 dose
`ranging and safety trials were also submitted. This NDA was submitted in electronic format as a
`hybrid CTD(i.e., CTD structure with PDF tables of contents), according to ICH and FDA
`guidelines for electronic submissions.
`
`Tables of Clinical Studies
`
`
`
`Ranibizumab
`Design (Sites)
`Dose(s)
`
`
`
`
`
`
`Randomized,
`Intravitreal
`0.3 mg (n=140),;
`Subjects with
`double-masked,
`
`
`
`
`injection q month,
`. .|Verteporfin
`
`double-sham
`0.5 mg (n=140),
`
`predominantly
`
`
`
`.
`PDT
`
`max. 24 injxns
`FVF2587g
`|
`active treatment-
`classic subfoveal
`sham injection
`
`
`over 2 yrs, or
`(tsham |
`
`
`controlled
`
`(n=143)
`neovascular
`injection)
`verteporfin PDT
`AMD
`J
`
`
`
`
`
`(US, Europe,
`q3mosas needed
`
`Australia
`
`
`
`Subjects with
`
`
`Intravitreal
`0.3 mg (n=238),
`minimally
`Randomized,
`
`classic or occult
`Sham
`
`0.5 mg (n=240),
`injection q mo.,
`double-masked,
`
`
`716
`sham-controlled
`sham injection
`max. 24 injxns
`injection
`subfoveal
`
`
`
`neovascular
`(n-238)
`
`(US)
`
`
`AMD
`
`Study
`
`| FVF2598g
`
`
`over 2 years
`
`Sham
`injection
`
`|
`
`184
`
`0.3 mg
`0.5 mg
`sham injection
`(Target: 61-62
`subjects per group)
`
`
`
`
`
`
`FVF3192g
`
`Randomized,
`double-masked,
`sham-controlled
`(US)
`
`FVF2508g
`
`Extension
`(US)
`
`
`
`
`
`
`
`Subjects with
`recurrent
`subfoveal CNV
`with or without
`classic CNV
`secondary to
`AMD
`
`Intravitreal
`injection q month
`for 3 doses
`(Day 0, Month 1,
`Month 2)
`followed by doses
`q 3 months
`(Mos. 5, 8, 11, 14,
`17, 20 and 23
`
`
`Intravitreal
`injections every 28
`days (+ 5 days)
`through October
`2006 or until 30
`days after product
` launch
`Intravitreal aT 0.3 mg to 1.0 mg
`
`|
`}
`
`|
`|
`
`nn _
`
`None
`
`70
`
`-|
`
`|
`
`0.5 mg (n=66)
`
`|
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 012
`
`Subjects with
`neovascular
`AMD who
`completed a
`Genentech Phase
`|
`1/2 ranibizumab |
`study
`|
`Randomized,
`injections at 2- or|escalating regimen
`Subjects with
`open-label,
`
`
`4-week intervals,
`with 7 total injxns
`neovascular;
`None
`multiple-dose
`| FVF2425g
`AMD
`max. of 5, 7 or 9
`(n=9);
`escalating
`
`0.3mg to 2.0 mg
`__total injections
`aI
`regimens
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 012
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 9 of 41
`
`Ranibizumab
`Dose(s)
`
`i}
`
`7|
`
`FVF2128¢
`
`FVF1770g
`
`,
`
`Ryness
`
`| CRFB002B
`,
`| 2201
`|
`
`Open-label,
`single-dose
`.
`escalation
`(US)
`
`Randomized,
`
`sham-controlled,
`combmation
`treatment
`(US)
`
`Open-label
`(Europe)
`
`
`
`Design(Sites)
`
`
`
`over 16 weeks
`
`
`
`
`
`
`
`0.3 mg (n=25),
`0.3 mg initial dose
`
`
`escalated to 0.5 mg
`for subsequent
`
`
`- doses 9n=28),
`usual care (n=11)
`
`
`
`
`0.05 mg (n=6),
`
`
`0.15 mg (n=6),
`0.30 mg (n=6),
`2
`0.50 mg (n=7),
`
`1.0 mg (n=2)
`Subjects with
`
`
`Verteporfin
`predominantly
`0.5 mg (n=106),
`Over 2 years,
`PDT(+sham
`classic
`sham injection
`injection)
`neovascular
`aT (n=56)
`
`AMD Py
`with verteporfin
`
`PDT q3mos, as
`—
`oe _.
`needed
`_
`
`
`
`0.3 mg
`Subjects with
`|
`.
`
`
`
`| CRFBOO2A|Open-label_|subfoveal CNV wone arget aitea 0.5 mg
`
`
`(Target: 42
`secondary to
`1201
`(Japan)
`84
`d
`y
`
`
`P
`_
`AMD
`||
`subjects per group
`Intravitreal
`Subjects with
`injections every
`32
`Verteporfin
`predominantly
`monthin
`3
`.
`
`combination with
`PDT
`classic subfoveal
`CNVsecoaty verteporfin PDT |
`
`
`
`escalating regimen
`with 9 total injxns
`(n=10);
`0.3 mg to 2.0 mg
`escalating regimen
`with 5 total injxns
`(n=10)
`
`
`
`Intravitreal
`injections q 4
`weeks, maximum
`of 8 total injections
`over 28 weeks, or
`usual care with
`crossover to
`ranibizumab
`treatmentafter 14
`weeks
`
`Single intravitreal
`woe
`injection
`
`Intravitreal
`injection q month,
`max. 24 injxns
`
`
`
`month
`
`_
`0.5 mg (n=30)
`
`subjects with
`classic
`neovascular
`AMD
`
`.
`
`Usual care
`
`d
`
`“
`
`es _
`
`ot
`See
`Subjects with
`neovascular
`AMD
`
`None
`
`27
`
`162
`
`
`
`Randomized,
`open-label,
`dose-escalation
`(US)
`
`
`single-masked,
`
`
`
`Review Strategy
`This review relies primarily on the results ofthe three Phase 3 trials submitted by the applicant.
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 013
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 013
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 10 of 41
`
`The submitted clinical study reports, clinical protocols and literature reports related to trials
`FVF2598g and FVF2587g were reviewed. The application is in electronic format as a hybrid
`CTD(i.e., CTD structure with PDF tables of contents), according to ICH and FDAguidelines for
`electronic submissions.
`
`Data Quality and Integrity
`Thereis no evidence that Phase 3 studies reviewed in this BLA were not conducted in
`accordance with acceptableclinical ethical standards.
`
`There were nosignificant problems identified Division of Scientific Investigations (DSI) audits
`that are likely to affect the data quality. The case report forms for the three studies were
`provided by Genentech, and these were reviewed for completeness and quality.
`
`Compliance with Good Clinical Practices
`The studies were conducted in accordance with the International Conference of Harmonization
`E6 Guidelines for Good Clinical Practice (GCPs), the Declaration of Helsinki and in compliance
`with relevant local and national regulations for informed consent and protection of subjectrights
`in the country of conduct.
`
`Beforeinitiation of the study, the original protocol, all protocol amendments, the informed
`consent documents andall supportive information were reviewed and approved by the
`appropriate ethics committees (EC)or institutional review boards (IRB) for each ofthe centers
`involved in the study. The studies began only after receiving written approval from each
`EC/IRB.
`
`Financial Disclosures
`The applicant has adequately disclosed financial arrangementswith clinical investigators as
`recommended in the FDA guidancefor industry on Financial Disclosure by Clinical
`Investigators.
`
`Thereis no evidence suggesting problemswith the integrity of the submitted data.
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics — See primary reviews.
`
`Pharmacodynamics — See primary reviews.
`
`Exposure-Response Relationships
`Theretinais the site of disease in neovascular AMD.Therefore, systemic ranibizumab
`concentrations after intravitreal administration are not expected to correlate with efficacy.
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 014
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 014
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 11 of 41
`
`INTEGRATED REVIEW OF EFFICACY
`The study designs of the three Phase 3 studies are included in the Primary Medical Officer’s
`Review. Additional analyses and cross comparisons between studies are presented below. It is
`recognized that there are potential risks in comparing across studies. With respectto treatment
`byan intravitreal route ofadministration, these studies utilized essentially the same population.
`
`
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 015
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 015
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 12 of 41
`
`
`
`The 0.5 dose was consistently more effective than the 0.3 dose and each were moreeffective than
`the control group. The slope ofthe best fit line between month 3 and month 12 demonstrated a
`two thirds reduced effect ofranibizumab whenthe product was administered every three months
`compared to monthly treatments. The month 3-12 slopes for sham were -.87, -.85, -.84. The
`month 3-12 slopes for the 0.5 dose monthly were +.23 and +.26. The month 3-12 slopefor the
`q3month injections was -.56. For the g3month injection, this becomes a 5 letter loss over the 9
`month period
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 016
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 016
`
`

`

`.
`
`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`.
`
`Page 13 of 41
`
`
`
`
`
`
`+
`
`40
`
`35
`
`Noted above, there is no correlation between OCTand visual acuity. Treatment with
`ranibizumab results in a thinner macula even when the visual acuity decreases. The month 12
`values illustrate this point. At month 12forthe ranibizumab 0.5 group, the mean macular
`thickness has its lowest value; howeverthe visual acuity is at its worst.
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 017
`
`60
`
`55
`
`50
`
`45
`
`eats
`:
`
`|
`
`,
`
`;
`
`i
`ee
`—4— Sham OCT
`—4—0.3 OCT
`
`0.5 OCT
`—#— Sham Visual Acuity fy
`2 —8— 0.3 Visual Acuity
`0.5 Visual Ac
`
`150
`
`170
`
`190
`
`210
`
`230
`
`250
`
`270
`
`a g
`
`cx
`o
`=
`-
`s
`s
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 017
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 14 of41
`
`
`
`L
`
`_)
`
`This graphillustrates that a substantially larger proportion ofpatients treated with ranibizumab
`injection develop thinner maculae and have improvedvisual acuity. While there is not a direct
`correlation betweenvisual acuity and macular thickness over the course of this study, there is a
`general tendencyfor patients treated with ranibizumab to do both. For anyindividualpatient,
`there is no significant correlation between macularthickness and visual acuity.
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 018
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 018
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumabinjection)
`
`(~
`
`LC
`
`Page 15 of 41
`
`7
`
`a
`
`This graph presents a comparison between a change in OCTandthe visual acuity at the next
`visit. Although not shown, data looks very similarfor predictions of visual acuity at visits after
`the next visit. The graphillustrates that macular thickness is not predictive of visual acuityat
`later visits.
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 019
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 019
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 16 of 41
`
`c
`
`L-
`
`This graphillustrates the variation in visual acuityfor any given macular thickness. Whileit is
`expectedthat thicker maculae will ultimately leadto poorvision, within the timeframes ofthis
`study, there is no direct correlation betweenvisual acuity and macular thickness. As a general
`rule, it appears that macular thickness below 200often leads to better vision.
`
`Best Available Copy
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 020
`
`APOTEX V. REGENERON IPR2022-01524
`REGENERON EXHIBIT 2024 PAGE 020
`
`

`

`Draft Deputy Division Director Memorandum
`Wiley A. Chambers
`BLA 125156 Lucentis (ranibizumab injection)
`
`Page 17 of41
`
`An attempt wasmadeto see if OCTcriteria or vision loss criteria might have aided in the
`decision to treat patients with Lucentis. Although noformalcriteria have been definedfor
`normality ofOCT, an increase in 100 microns might be considered the smallest change reliably
`available to use as a basis for treatment.
`In addition, although a 15 letter loss is the smallest
`clinically significant change, a single line change(5 letters) is commonly reportedfor safety
`parameters and was therefore investigated as a small visual acuity change. Theresults are
`listed below:
`
`Percentage of Patients Meeting particular OCT or Vision Loss Criteria
`
`OCTIncreased byat least 100 or Vision Loss by 5 or moreletters
`Month 2
`Month 3
`Month 5
`Month 8
`Month 12
`64%
`53%
`75%
`75%
`78%
`19%
`38%
`51%
`54%
`59%
`5%
`30%
`43%
`54%
`54%
`
`OCT Increased byat least 100
`Month 2
`Month 3
`Month 5
`22%
`11%
`22%
`0%
`5%
`16%
`0%
`0%
`10%
`
`Month 8
`17%
`16%
`16%
`
`Month 12
`14%
`11%
`8%
`
`Vision Loss by 5 or more letters
`Month2
`Month 3
`Month5
`50%
`4T%
`69%
`19%
`35%
`41%
`5%
`30%
`38%
`
`Month 8
`69%
`46%
`54%
`
`Month 12
`75%
`59%
`51%
`
`Sham
`0.3
`0.5
`
`Sham
`0.3
`0.5
`
`Sham
`0.