292
`
`Correspondence
`
`EXHIBIT 18
`wrr. KU banbJ
`DATE 3-lV-)
`KRAMM COURTREPORflNG
`
`there was no significant corresponding improvement in
`vision, representing likely underlying macular
`ischaemia.
`There have been previous case reports of two
`patients achieving a beneficial effect in both eyes from
`the unilateral injection of ranibizumab for uveitis-
`related macular oedema,3 and a case of bilateral
`beneficial effect of both unilateral ranibizumab and
`bevacizumab in a patient with branch retinal vein
`occlusion.4
`Our case suggests that unilateral ranibizumab can
`have an effect on the fellow non-injected eye in a patient
`with diabetic macular oedema. This is contrary to
`previous reports, which indicate that such an effect is
`only seen with bevacizumab. We suggest clinicians be
`aware of this possible effect to determine whether there
`are further similar cases.
`
`Conflict of interest
`
`The authors declare no conflict of interest.
`
`References
`
`I Hanhart J, Tiosano L, Averbukh 8, Banin E, Hemo 1,
`Chowers 1. Fellow eye effect of unilateral intravitreal
`bevacizumab injection in eyes with diabetic macular edema.
`Eye 2014; 28: 646-653.
`2 Bakbak B, Ozturk BT, Gonul S. Yilmaz M, Gedik S.
`Comparison of the effect of unilateral intravitreal bevacizumab
`and ranibizumab injection on diabetic
`macular edema of the fellow eye. I Ocul Pharmacol Ther
`2013; 29: 728-732.
`3 Acharya NR, Sittivarakul W, Qian V. Hong KC, Lee SM.
`Bilateral effect of unilateral ranibizumab in patients
`with uveitis-related macular edema. Retina 2011; 31:
`1871-1876.
`4 Wu Z, Sadda SR. Effects on the contralateral eye after
`intravitreal bevacizumab and ranibizumab injections:
`a case report. Ann Acad Med Singapore 2008; 37: 591-593,
`
`NS Sharma, JM Ong and J-L Ooi
`
`Medical Retina, Cambridge University Hospitals NHS
`Trust, Addenbrooke's Hospital, Cambridge, UK
`E-mail: neilsss@hotmail.com
`
`Eye (2015) 29, 291-292; doi:1O.1038/eye.2014.265;
`published online 14 November 2014
`
`available anti-VEGF compounds likely have an effect on
`the fellow eye to some extent. Most probably, the
`characteristics of that contralateral effect depend, among
`other parameters, on the precise molecular structure of
`the injected drug.
`Ranibizumab and bevacizumab differ in their
`molecular weight, structure, and pharmacokinetics.2
`Ranibizumab is a 48-kDa antigen-binding fragment,
`which lacks a fragment crystallizable (Fc) region and
`is rapidly cleared from the systemic circulation.3 Our
`retrospective study suggests clinically meaningful
`contralateral effect in more than a quarter of patients
`treated with bevacizumab, a 150-kDa monoclonal
`antibody containing an Fc region.4 Contralateral effect
`might be more frequently observed with bevacizumab
`than ranibizumab due to the Fc region-dependent
`active transport of bevacizumab to the systemic
`circulation. In accordance with that, results from
`the IVAN study, conducted in AMO patients,
`underlines the difference in pharmacokinetics between
`bevacizumab and ranibizumab: the decrease in
`serum-free VEGF from baseline at 12 months is
`significantly greater with bevacizumab compared
`with ranibizumab.5 Yet, some of our patients treated
`with ranibizumab for DME also demonstrated a fellow
`eye effect (unpublished observations). As highlighted
`by the case presented by Sharma et all systemic
`passage of ranibizumab may well result in effect on
`the fellow eye. Interestingly, such a contralateral
`influence of ranibizumab has been described in
`conditions in which inflammation has a pivotal role
`(uveitis, retinal vein occlusion, and diabetes-related
`macular edema).
`Another point that certainly merits to be closely
`observed is the potential contralateral effect of
`intravitreally injected aflibercept, a 11O-kDa fusion
`protein that, like bevacizumab and unlike ranibizumab,
`contains an Fc region.
`Contralateral effects are important as unilateral
`injections may suffice to treat bilateral edema in certain
`patients. This phenomenon also underscores potential
`systemic effects of intravitreal injection of anti-VEGF
`compounds. Taken together, the case presented by
`Sharma et a!, combined with our findings on
`bevacizumab, and other reports on the subject suggest
`that the incidence, extent, and consequences of such
`fellow eye effect should be carefully evaluated in a
`prospective trial.
`
`Conflict of interest
`
`JH declares no conflict of interest. IC served as an
`advisor/consultant for Novartis, Bayer, Allergan, and
`LycoRed; has received grants for clinical research from 1SF.
`
`Sir,
`Fellow eye effect of unilateral intravitreal anti-VEGF
`injections in eyes with diabetic macular edema
`
`References
`
`We thank Sharma et all for reporting a case of significant
`bilateral reduction in macular thickness following
`unilateral ranibizumab therapy for diabetic macular
`edema (DME). This case corroborates our feeling (based
`on our research and experience in the clinic) that all
`
`1 Sharma NS, Ong JM, Ooi J-L. Re: 'Fellow eye effect of
`unilateral intravitreal bevacizumab injection in eyes with
`diabetic macular edema'. Eye 2015; 29: 291-292-
`2 Avery RL, Casteilarin AA, Steinle NC, Dhoot DS,
`Pieramici DJ, See R et al. Systemic pharmacokinetics
`following intravitreal injections of ranibizumab,
`bevacizumab or aflibercept in patients with neovascular
`
`Eye
`
`Mylan Exhibit 1104
`Mylan v. Regeneron, IPR2021-00880
`Page 1
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`

`

`Correspondence
`
`293
`
`AMD. Br! Ophthalmol 2014; e-pub ahead of print 7 July 2014;
`doi:1O.fl36/bjophthalmol-2014-305252.
`3 Xu L, Lu 1, Tuomi Let al. Pharmacokinetics of ranibizumab
`in patients with neovascular age-related macular
`degeneration: a population approach. Invest Ophthalmol
`Vis Sri 2013; 54: 1616-1624.
`4 Hanhart J, Tiosano L, Averbuckh E, Banin E, Hemo I,
`Chowers I. Fellow eye effect of unilateral intravitreal
`bevacizumab injection in eyes with diabetic macular edema.
`Eye 2014; 28: 646-653.
`5 IVAN Study Investigators, Chakravarthy U, Harding SP,
`Rogers CA, Downes SM, Lotery AJ et al. Ranibizumab
`versus bevacizumab to treat neovascuJar age-related
`macular degeneration: one-year findings from the
`IVAN randomized trial. Ophthalmology 2012; 119(7):
`1399-1411.
`
`J Hanhart1'2 and I Chowers2
`
`'Department of Ophthalmology, Shaare Zedek
`Medical Center, Jerusalem, Israel
`2Department of Ophthalmology, Hadassah-Hebrew
`University Medical Center, Jerusalem, Israel
`E-mail: chowers@hadassah.org.il
`
`Eye (2015) 29, 292-293; doi:10.1038/eye.2014.261;
`published online 14 November 2014
`
`Sir,
`Is accelerated corneal cross-linking for keratoconus the
`way forward? Yes or No
`
`While I congratulate the Journal for encouraging such
`interesting debates and the authors for their hard work in
`presenting their points of view, I feel it is necessary to
`point out two inaccuracies presented and repeated in
`both articles. 1,2
`The first is equating the degree, depth, and safety of
`cross-linking to the depth of the demarcation line. There
`is currently no evidence to support this direct
`correlation. The so-called stromal demarcation line, first
`described by Seiler and Hafezi,3 can be easily
`delineated by anterior segment optical coherence
`tomography, has been shown to possibly be shallower
`in older patients and those with more severe ectatic
`disease.4 It has been found to be thicker centrally and
`thinner peripherally5 and possibly related to an increased
`density of the extracellular matrix.6 Although a deeper
`demarcation line has been associated with a larger
`decrease in corneal thickness,7 its depth has not been
`shown to be correlated to either visual or keratometric
`changes at 6 months post-operatively.4 It may simply
`represent natural wound healing responses rather than
`delineate the true area between cross-linked and uncross-
`linked tissue. Clearly a lot more research is required to
`ascertain the true nature of this demarcation line and its
`relationship with the actual cross-linking process.
`
`Finally, in both articles it is stated that keratoconus in
`its early stages is a posterior corneal disease. Although
`posterior corneal curvature changes can indeed be
`detected before anterior alterations in sub-clinical
`disease, this is almost certainly due to the epithelium
`masking early anterior changes. This has been elegantly
`demonstrated by Reinstein et a!8 using high-resolution
`ultrasound.
`
`Conflict of interest
`
`The author declares no conflict of interest.
`
`References
`
`I Tsatsos M, MacGregor C, Kopsachilis N, Anderson D.
`Is accelerated corneal collagen cross-linking for
`keratoconus the way forward? Yes. Eye (Lend) 2014; 28(7):
`784-785.
`2 MacGregor C, Tsatsos M, Hossain P. Is accelerated corneal
`collagen cross-linking for keratoconus the way forward?
`No. Eye (Land) 2014; 28(7): 786-787.
`3 Seiler T, Hafezi F. Corneal cross-linking induced
`stroinal demarcation line. Cornea 2006; 25(9): 1057-1059.
`4 Yam JC, Chan CW, Cheng AC. Corneal collagen cross-
`linking demarcation line depth assessed by Visante OCT
`After CXL for keratoconus and corneal ectasia. I Refract Surg
`2012; 28(7): 475-481.
`5 Kymionis GD, Grentzelos MA, Plaka AD, Stolanovic N,
`Tsoulnaras KI, Mikropoulos DC et al. Evaluation of the
`corneal collagen cross-linking demarcation line profile
`using anterior segment optical coherence tomography.
`Cornea 2013; 32(7): 907-910.
`6 Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S.
`Caporossi T, Tommasi C Cf al. Treatment of
`progressive keratoconus by riboflavin UVA induced
`cross linking of corneal collagen: ultrastructural
`analysis by Heidelberg retinal tomography II in vivo
`confocal microscopy in humans. Cornea 2007; 26(4):
`390-397.
`7 Doors M, Tahzib NC, Eggink FA, Berendschot Tr,
`Webers CA, Nuijts RM. Use of anterior segment optical
`coherence tomography to study corneal changes after
`collagen cross-linking. Am J Ophthalmol 2009; 148(6):
`844-851.
`8 Reinstein DZ, Archer fl, Gobbe M. Corneal epithelial
`thickness profile in the diagnosis of keratoconus. I Refract
`Surg 2009; 25(7): 604-610.
`
`DIPS O'Brart
`
`Department of Ophthalmology, Guy's and St Thomas
`NHS Foundation Trust, London, UK
`E-mail: davidobrart©aol.com
`
`Eye (2015) 29, 293; doi:10.1038/eye.2014.274; published
`online 14 November 2014
`
`Eye
`
`Mylan Exhibit 1104
`Mylan v. Regeneron, IPR2021-00880
`Page 2
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