`
`January 2010 Volume 94 Issue 1
`
`1
`
`FEB 0 I 2010
`LibraryDateReceivea
`Ophthalmology
`
`Shawnee Mission Medica! Center Medical Library
`
`British Journal of
`
`
`
`bjo.bmj.com
`
`BMjJl| Journals
`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 1
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2119
`Page 1
`
`

`

`1
`
`Ocular anaesthesia and the never-ending story
`P Athanasiov, T Henderson
`
`
`
`41 Macular morphology and visual acuity after
`macular hole surgery with or without internal
`limiting membrane peeling
`U CChristensen, K Kroyer, B Sander,
`T MJorgensen, M Larsen, M la Cour
`
`Review
`2
`Ranibizumab (Lucentis) in neovascular
`age-related macular degeneration: evidence
`from clinicaltrials
`P Mitchell, J-F Korobelnik, P Lanzetta, F G Holz,
`New patternsofretinalcollateral circulation are
`C Priinte, U Schmidt-Erfurth, ¥ Tano, S Welf
`exposed byaretinal functional imager (RFI)
`
`G Landa, R B Rosen
`
`48
`
`Si@s
`
` Subretinal coapplication of recombinant tissue
`plasminogen activator and bevacizumabfor
`neovascular age-related macular degeneration
`with submacular haemorrhage
`F Treumer, C Klatt, J Roider, J Hillenkamp
`
`Relationship between different fluorescein and
`indocyanine green angiography features in
`multiple evanescent white dot syndrome
`R dell‘Omo, R Wong, M Marino,
`K Konstantopoulou, C Pavesto
`
`Global issues
`14 Mapping trachomain Nasarawa and Plateau
`States, central Nigeria
`J D King, N Jip, Y S Jugu, A Othman,
`A F Rodgers, D Y Dajom, E Miri, P M Emerson
`
`64
`A comparison between microperimetry and
`standard achromatic perimetry of the central
`20=Increased hyperopia with ageing based on
`visual field in eyes with glaucomatous
`cycloplegic refractions in adults: the Tehran Eye
`paracentral visual-field defects
`Study
`V C Lima, T S Prata, C G V De Moraes, J Kim,
`H Hashemi, R Iribarren, 1 G Morgan, M
`KhabazKhoob, K Mohammad, A Fotouhi
`WSeiple, R B Roseu, J M Liebmann, R Ritch
`
`Innovations
`24
`Computer simulation-assisted rotational
`autokeratoplasty with pupillary enlargement for
`74~~‘Efficacy andtolerability of bimatoprost versus
`management of cases with partial corneal
`travoprostin patients previously on latanoprost:
`opacification
`a 3-month, randomised, masked-evaluator,
`T Agarwal, N Sharma, V Jhanji, R B Vajpayee
`multicentre study
`J A Kammer, B Katzman, S L Ackerman,
`DA Hollander
`
`68
`
`The sensitivity and specificity of Heidelberg
`Retina Tomograph parameters to glaucomatous
`progression in disc photographs
`V Saarela, A Falck, P J Atraksinen, A Tuulonen
`
` Editorial
`
`80
`
`Using diurnal intraocular pressure fluctuation to
`assess the efficacy of fixed-combination
`latanoprost/timolol versus latanoprostor timolol
`~ monotherapy
`R Varma, L-] Hwang, J W Grunden, G W Bean
`
`MORE CONTENTS »
`
`This article has been chosen by the Editor to ba of special interest
`or importance andis freely available online,
`
`Articles carrying the Unlocked Logo are freely avaiable online
`under the BMJ Joumels unlocked scheme.
`See http://bjo.bmj.convinfo/unlocked.dtl
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`GO PE. comme on runeanen eres
`
`g (
`
`network
`
`his joumalis a member af and subscnbesto the pnnciples of the
`Committee on Publication Ethics
`www.
`i
`@ equator
`
`i T
`
`Cover illustration
`26
`~All for a drop: Undines and drop bottles
`R Keeler, A D Singh, H S Dua
`
`Original articles
`Clinical science
`28
`=A novel Ocular Anaesthetic Scoring System,
`OASS,tool to measure both motor and sensory
`function following local anaesthesia
`J Cehajic-Kapetanovic, P N Bishop, S Liyanage,
`T King M Muldoon, | M Wearne
`
`33
`
`36
`
`Intraocular pressures after ketamine and
`sevoflurane in children with glaucoma
`undergoing examination under anaesthesia
`L Jones, V Sung, G Lascaratos, H Nagi,
`R Holder
`
`=A pilot randomised controlled trial comparing
`the post-operative pain experiencefollowing
`vitrectomy with a 20-gauge system and the
`25-gauge transconjunctival system
`L Wickham, C Bunce, A S Kwan, ] Bainbridge,
`G W Aylward
`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2119
`Page 2
`
`

`

`| BJO January 2010
`
`Volume 94 Number 1
`
`ycey
`
`85=Theeffect of s economic deprivation on
`
`115
` Peripapillary retinal nerve fibre layer thickness
`
`
`profile in subjects with myopia m
`red using
`severity of glaucomaat presentation
`the Stratus optical coherence tomography
`
`88
`
`training of cerebral blindness patients
`Visual
`gradually enlarges the visual
`field
`
`121 Ophthalmological findings in children and young
`adults with genetically verified mitochondria
`disease
`
`97
`
`Scope of super-resolution
`
`in central vision
`
`101
`
`ring
`Evaluation of the impact of intracorneal
`life of
`of
`segments implantation on the quality
`patients with keratoconus using the NEI-RQL
`(National Eye Institute Refractive Error Quality
`of
`life)
`instrument
`
`106
`
`of
`Evaluation
`biometer
`1 PIC yp
`
`the Lenstar LS 900 non-contact
`|
`
`128
`
`A prospective comparison of fine-needle
`
`aspiration cytopathology and histopathology in
`the diagnosis of orbital mass lesions
`
`Education
`131
`Papilloedemaandvision loss with elevated
`cerebrospinal fluid protein in
`a patient with
`systemic lupus erythematosus: diagnosis and
`management challenges
`
`111
`
`Endophthalmitis following openglobe injury
`
`PostScript
`133 Letters
`
`139 Mailbox
`
`this first class journalis just a few clicks away.
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`Whynot recommendthe journal to your librarian or better
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`
`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`IPR2023-00884
`Samsunget al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2119
`Page3
`
`

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`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 4
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2119 Page 4
`
`

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`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 5
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2119 Page 5
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`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 6
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2119 Page 6
`
`

`

`b) ANCHOR; Monthly regimen; 96.9% PC, 2.8% MC, 0.2% ONC
`
`aa auY
`
`-ae- Ranibizumab 0.3 mg
`—@ Ranibizumab 0.5 mg
`-@- Verteporfin POT
`3
`6
`
`9
`
`0
`
`15
`
`18
`
`21
`
`24
`
`12
`Time (months)
`Monthly vs quarterly maintenance; 20.7% PC, 40.2% MC, 39.1% ONC
`16
`
`
`
`ohBeERRE
`
`
`
`0
`
`Fh-------------- ~~ = =oe enene ene eee nsesesccwoece
`
`10
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`eS
`8
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`§ -10
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`-15
`=
`=
`=te- Ranibizumab 0.3 mg
`s
`-20472e- Ranibizumab 0.3 mg quarterly
`Ranibizumab 0.5 mg quarterly
`—@ Ranibizumab0.5mg ~
`-“@- Sham injection
`Ranibizumab 0.3 mg monthly
`* -
`3
`6
`12
`3
`6
`0
`Ranibizumab
`Time (months)
`Time (months)
`Ranibizumab
`injections
`4
`4
`+
`t
`4
`
`
`
`
`
`(quarterly)
`f) SUSTAIN;individualised maintenance with monthlyvisits
`€) PrONTO; individualised maintenance with monthly visits;
`17.5% PC, 57.5% MC, 25.0% ONC
`
`0
`
`9
`
`15
`
`18
`
`21
`
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`9
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`injections $¢t RGalttgre¢ 4 f eR NL
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`15
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`rue
`10
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`5
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`=
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`
`32=83
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`s2>=
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`2 as55=
`
`—&- Aanibizumab 0.5 mg
`
`720
`=:te- Ranibizumab 0.3 mg
`
`12
`9
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`Tine ences=
`Ranibizumab
`Renibizumab THnetieonehe)—.cVe—ceeX__x\m\>
`
`injections
`cos
`Incividualised dosing with monthly visits
`injections
`t
`t
`4
`individualised desing with monthly visits
`
`The LOCK method was used to wnoute rissing data
`Vertical bars are +) standard error of the mean
`LOCF siast onservaton camec forward; PC=precominanty classic; POT=photodynamic therapy: MG=minimally classic: ONC=occult (wih no classic)
`
`Figure 1 Mean change from baseline in best-corrected visual acuity by month for (A) MARINA, (B) ANCHOR,(C) PIER, (D) EXCITE, (E) PrONTO,(F)
`SUSTAIN ((A) Copyright© 2006 Massachusetts Medical Society. All rights reserved; (B) reprinted from Ophthalmology 2009, 116, Brown etal,
`Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: 2-year results of ANCHOR Study, 57-65,
`Copyright 2009, with permission from Elsevier; (C) reprinted from Regillo et a/, Ranibizumab (Lucentis)in treatment of neovascular age-related macular
`degeneration (AMD): 2-year results of PIER study, poster P0459 presented at the AAO 2007; (E) reprinted from Am J Ophthalmol! 2007, 143, Fung etal,
`An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular
`degeneration, 566-83, Copyright 2007, with permission from Elsevier).
`
`Br J Ophthalmol 2010;94:2-13. doi:10.1136/bjo.2009. 159160
`
`5
`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 7
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc.
`Exhibit2119
`Page 7
`
`a) MARINA; Monthly regimen; 0.19% PC, 63.0% MC, 36.9% ONC
`
`
`
`
`
`
`
`Meanchangeinvisualacuity(letters)
`
`-
`
`52
`3so
`
`a a><
`
`¢
`
`&s
`
`-=SC
`
`=~ Ranibizumab 0.3 mg
`—# Ranibizumab 0.5 mg
`-@- Sham injection
`3
`6
`
`9
`
`0
`
`16
`
`18
`
`12
`Time (months)
`c) PIER; Quarterly maintenance; 18.0% PC, 38.6% MC, 43.0% ONC
`
`
`
`
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`
`
`
`
`
`
`Meanchangeinvisualacuity(letters)
`
`21
`
`24
`
`d) EXCITE;
`
`8@
`
`3e
`
`5 8
`
`

`

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`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 8
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2119 Page 8
`
`

`

`
`aaa
`
`Maintenance phase
`
`(letters) Do2Bee Sioa
`Meanchangeinvisualacuity
`
`
`
`
`6+Bdeti SF Se 10 aie
`
`
`
`the first 3 months; or >100 um increase in CRT from the
`previous lowest measurement during thefirst 3 months.” ® At
`12 months, mostof the first 3 months’ VA gain was maintained
`(figs 1F, 4; table 3), Although only an interim analysis of 69
`patients, these results suggest that flexible, guided dosing with
`fewer ranibizumab injections and monthly monitoring can
`maintain efficacy outcomes. However, some VA loss occurred
`after month 3, whereas fixed monthly injections resulted,
`in
`further VA improvement during the maintenance phase.
`In summary, ranibizumab monthly intravitreal
`injections
`demonstrated the best VA outcomes. Studies with less than five
`injectionsin thefirst 12 months generally showed the weakest
`efficacy benefits (tables 2, 3; figs 1, 4), although results were
`variable. PRONTO and SUSTAIN showed that monthly monitor-
`
`ing was required to maintain efficacy benefits, compared with
`Time (months)
`SAILOR Cohort 1, which had mandatory quarterly follow-up
`visits, although more frequent
`follow-up was possible and
`performed for manypatients.
`
`
`
`Figure 2 Mean change in visual acuity from baseline (observed cases):
`difference between each monthly visit for 0.5 mg of ranibizumab in MARINA
`and ANCHOR(data onfile, Novartis Pharma AG, Basel, Switzerland).
`
`Clinical recommendation (level | evidence)
`>» A monthly regimen of ranibizumab intravitreal injection
`demonstrated the best VA outcomesin theclinicaltrials.
`
`investigated three consecutive monthly
`1
`SAILOR Cohort
`injections followed by quarterly monitoring visits and injections
`guided by VA (more than five-letter loss from the previous
`Clinical recommendation(levelIll evidence)
`highest VA score) and OCT criteria,
`if available (>100 um
`
`increase in CRT from the previous lowest measurement).” >» Whenamonthly regimenis notpossible, a flexible strategy
`with monthly monitoringis feasible. Benefits could be less
`Additionalvisits/injections were possible if required. The mean
`than with monthly treatment.
`VA changeincreased from baseline overthefirst three injections
`>» Frequent monitoring aims to detect active disease from:
`but then decreased (fig 4; table 3) to a mean gain overbaseline
`of 2.3 letters for both ranibizumab doses, a better result than in
`history, VA assessments,slit-lamp examinations and OCT.
`PIER, but suboptimal when compared with ANCHOR and
`FA is generally not essential at this stage but could be
`considered, particularly if the retinal examination does not
`MARINA.” These results indicated that quarterly visits were
`explain recent or progressive VA deterioration (FA may
`insufficient to monitor and capture disease progression.
`Interim results are available from the SUSTAIN trial of three
`identify recurrent leak or CNV enlargement).
`IE active disease is present or recurs, additional treatment
`consecutive monthly injections, then monthly monitoring and
`should be initiated quickly to improve functional outcomes.
`additional treatment guided by the followingcriteria: more than
`If the disease is inactive, retreatment is not necessary
`five-letter loss in VA from the previous highest VA score during
`
`»
`
`>
`
`—a&— Maintained initial gain of >0 at Month 3 (n=16, 40% within initial gainers)
`--@--
`Initial gain not maintained (n=24, 60% within initial gainers)
`
`Figure 3 Mean change in visual acuity
`from baseline for three subgroups of
`patients in the PIER trial showing that
`40% of initial responders retained their
`initial visual acuity gain during the
`maintenancephase, although the
`quarterly regimen did not permit this for
`the remaining 60% ofinitial responders
`(data on file, Novartis Pharma AG, Basel,
`Switzerland).
`
`15——® - No initial gain (no gain at Month 3) (n=21)
`Meanchangeinvisualacuity(letters)
`
`
`
`
`Vertical bars are +1 standard error of the mean.
`
`Time (months)
`
`Br J Ophthalmol 2010;94:2-13. doi:10.1136/bjo.2009.159160
`
`7
`
`Mylan Exhibit 1030
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`Page 9
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2119
`Page9
`
`

`

`Figure 4 Mean change in visual acuity
`Visite
`Maintenanceinjections
`from baseline at the end of the loading
`
`Solid lines = Fixed monthly
`Fixed monthly
`phase (@) and at 12 months (arrowhead)
`Z
`Ss
`against the numberof injections during
`
`
`9 months:the maintenance phaed Dashed lines=Fixed quarterlyFixed quarterly
`(ranibizumab 0.5 mg data unless
`
`tA
`
`10
`
`g@ 9
`8
`= i
`
`=s
`
`=oo
`
`e
`
`ok
`
`4
`3
`
`3a
`
`e
`
`> &e
`
`s
`Da
`a
`
`5c
`
`2
`
`oO
`Do
`=f
`
`0
`
`1 2
`
` ————_ Individualised dosing
`
`1 PIER
`
`Numberof injections during maintenance phase
`
`>
`
`In both cases, patients should be reviewed at each following
`month using the same assessments, with treatment
`administered only if active disease is present.
`» Continued monthly follow-up (with an injection if
`required) can be recommended,particularly during thefirst
`12 months, in order to detect active disease.
`If the clinical signs remain quiescent for a longer period,
`extending the follow-upintervals may then bejustified.
`
`>
`
`How frequently is ranibizumab therapy needed after 2 years?
`In the HORIZONextension trial of MARINA and ANCHOR,
`61%of patients needed someadditional treatments in the third
`year; overall better VA and anatomical outcomes after 2 years
`predicted a longer time to retreatmentin this period. Someloss
`of VA gain occurred, presumably related to undertreatment in
`the extension period.”
`
`Is treatment with ranibizumab safe?
`In a review of safety data from the 3252 patients in ANCHOR,
`MARINA, PIER and SAILOR(level I evidence) who received
`over 28 500 intravitreal ranibizumab injections, ranibizumab
`was found to have a high benefit-risk ratio for
`treating
`neovascular AMD.“
`Per-injection
`rates
`of
`presumed
`endophthalmitis (0.05%) or serious intraocular inflammation
`(0.03%) were low.
`A low incidence of serious ocular adverse events has been
`demonstrated for 0.5 mg of ranibizumab (table 4). In MARINA
`and ANCHOR (24-month data),
`the most common were:
`
`1.4% in
`0.7% in
`
`(1.3% in MARINA;
`(1.3% in MARINA;
`
`presumed endophthalmitis
`ANCHOR)
`and
`uveitis
`ANCHOR).” ** 4
`In MARINA and ANCHOR,the incidence of systemic
`adverse events was similar across treatment groups. During
`the 24-month treatment period,
`the rates of Antiplatelet
`Trialists’ Collaboration (APTC)® arterial
`thromboembolic
`events (ATEs), including non-fatal myocardial infarction, non-
`fatal stroke and death from a vascular or unknowncause, were:
`3.8%(sham), 4.6%(0.3 mg of ranibizumab) and 4.6%(0.5 mgof
`ranibizumab) in MARINA; and 4.2% (verteporfin PDT), 4.4%
`(0.3 mg of ranibizumab) and 5.0% (0.5 mg of ranibizumab) in
`ANCHOR.” *™ In PIER, a low rate of serious ocular adverse
`events and no ATEs were observed with ranibizumab(table 4).*
`An interim SAILORsafety analysis showed a trend for an
`increase in the incidence of stroke in the 0.5 mg group. The
`incidenceof stroke in the final analysis was 0.7%(0.3 mg) and
`1.2% (0.5 mg), but the numerical difference between the two
`doses wasnotstatistically significant. Incidence of stroke was
`higher with pre-existing risk factors, particularly a previous
`stroke history (2.7%(0.3 mg) and 9.6% (0.5 mg)) or arrhythmia.
`AMDhas previously been associated with a higherrisk of
`stroke. In a retrospective analysis of 15 771 patients with
`neovascular AMD and 46 408 matched controls, the incidence of
`ischaemic stroke was 3.5% and 3.6%,
`respectively, which
`increased to 35.1% when there was a history of previous
`ATEs.” The observed incidence of stroke with ranibizumab was
`low in these trials, but needs to be continuously monitored in
`ongoing postmarketing studies. Nevertheless, the benefit-risk
`
`Br J Ophthalmol 2010;94:2-13, doi:10.1136/djo.2009.159160
`
`8
`
`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 10
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2119
`Page 10
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`Mylan Exhibit 1030
`Mylan v. Regeneron, IPR2021-00880
`Page 11
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2119 Page 11
`
`