ax
`
`iBeenieea
`-SciTirta
`etNNes
`
`exple7MOTImeatalaeTomatoMIESEANARTsa ~~
`
`47.0).1
`
`a
`
`iabetic macular edema (DME)is the leading cause
`ofvision loss in the working-age population in the
`developed world.'? The average ageat diagnosisis
`just over 50 years, and DMEhasa significant impact
`both individually and economically, with a high
`treatment burden.'*5 Consequently, thereis a strong ratio-
`nale for developing treatments for DME that provide mean-
`ingful visual benefits while minimizing the monitoring and
`treatment burden.
`
`INITIAL THERAPY OPTIONS
`Anti-VEGFagentsare thefirst-line treatmentfor visual
`impairmentassociated with DME, and they can help
`patients achieveclinically meaningful BCVAgains of up to
`13 letters.*"° However, not every patient respondsto ther-
`apy; as many as 40%ofparticipants in pivotal trials do not
`reach a VA threshold of 20/408
`A key challenge with current anti-VEGF agentsis the treat-
`mentfrequency required to achievevision gains. Some phase
`3 trials evaluating anti-VEGF agents in DME used continuous
`monthly dosing, and even the individualized dosing regi-
`men used in the DRCR Retina Network's Protocol T study
`required a medianof nine to 10 injectionsin the first year.®"°
`Frequentinjections maybe difficult to maintain, and under-
`treatmentleads to suboptimal outcomes.In a large observa-
`tional study, DMEpatients receiving four or fewer injections
`in thefirst year of treatment with ranibizumab (Lucentis,
`Genentech) gained only 0.5 letters, while those receiving five
`or moreinjections gained a mean 6.9 letters from baseline."!
`Investigational therapies with anti-VEGF activity—eg,
`faricimab (Roche), a bispecific anti-VEGF and anti-angiopoi-
`etin 2 antibody, and KSI-301 (Kodiak Sciences), an anti-VEGF
`
`34 RETINA TODAY | SEPTEMBER 2021 Exhibit 2262
`Page 01 of 03
`
`antibody-biopolymer conjugate—aim to address undertreat-
`mentby achieving increased durability of action. This results
`in less frequent treatmentin the maintenance phase (up
`to every 16 weeks with faricimab and every 24 weeks with
`KSI-301). However,pivotal trials investigating these agents
`still include three orfourinitial monthly treatments, result-
`ing in up tosix injectionsin thefirst year of treatment, even
`with the longest intervals.'2"3
`In patients who do notreceive adequate benefits from
`anti-VEGF therapy,alternative treatments such as one or
`more preparations ofcorticosteroids may be an option.®”
`
`We aa
`
`> Diabetic macular edema (DME) comeswith a high
`treatment burden, pushing researchers to develop
`new treatments that provide meaningful visual
`benefits while minimizing the monitoring and
`treatment burden.
`
`> Sustained-release formulations of corticosteroids for
`DMEoffer a numberof potential benefits, including
`less frequent administration and, potentially,
`reduced fluctuations in retinal thickness.
`
`> A novel sustained-release steroid formulation of
`dexamethasone incorporated into biodegradable
`microspheres can beinjected suprachoroidally.
`
`Mylan v. Regeneron, IPR2021-00881 U.S. Pat. 9,254,338, Exhibit 2262
`
`Exhibit 2262
`Page 01 of 03
`
`

`

`CASE STUDY
`
`In this 78-year-old woman with chronic macular edema, a dexamethasoneintravitreal implant was
`removed after its migration into the anterior chamber led to significant IOP increase and corneal edema.
`Twosubsequent monthly sub-Tenoninjections of a triamcinolone 40 mg had little effect, and central
`macular thickness (CMT) remained at 551 um.
`A semiautomated ocular administration device was used to deliver triamcinolone 2.4 mg suspension
`to the suprachoroidal compartment.
`The procedure was successful, with no hemorrhage or reflux, and CMT decreased to 344 wm after
`10 days. At 20 days, CMT reductions were maintained,and the patient had gained around4 lines of
`vision compared with baseline.
`
`DIABETIC EYE DISEASE <
`
`Pre-treatment
`
`;
`
`1 day post-treatment
`
`Two sub-Tenon injectionsin this period
`0.72
`07
`sas
`pes
`
`600>—————____§ ——$—
`550
`— -
`—$—__56°
`S51 0.65
`0.6
`500
`
`650
`
`Suprachoroidal
`Injection
`
`~4 lines of
`visual gain
`
`4°25
`
`444
`
`377
`
`ne
`03
`03
`
`344
`0
`
`)
`ue
`
`=
`& 450
`5 400
`0
`350
`300
`250
`~O-Average CM
`~<-Visual
`
`200 Lar
`-34 -32 -30 -28 -26 -24 -22 -20
`-18
`-16 -14
`-12
`-10
`8
`4
`4
`2
`0
`2
`4
`6
`8
`10
`12
`14
`16
`18
`2%
`Days from suprachoroldalinjection
`
`0.8 (20/125)
`
`
`10 days post-treatment
`
`
`
`Visualacuity
`
`Corticosteroids have both antiinflammatory and
`antiedematous properties. They can help to address the
`pathogenesis of DME bylimiting the permeability of the
`blood-retina barrier to reduce edema, downregulating VEGF
`expression, acting on inflammatory processes, and inhibiting
`prostaglandin and proinflammatory cytokine production.'4
`Sustained-release formulations of corticosteroidsfor
`DMEoffer a numberof potential benefits. Less frequent
`administration reduces the patient’s treatment burden, and
`consistent, gradual steroid release should reduce fluctuations
`in retinal thickness and maintain visual benefits.
`Twosustained-release steroids are currently approvedin
`the United States and Europefor use in patients with DME:
`the dexamethasoneintravitreal implant 0.7 mg (Ozurdex,
`Allergan) and the fluocinolone acetonideintravitreal
`implant 0.19 mg (Iluvien, Alimera Sciences).
`In phase 3 trials of the dexamethasoneintravitreal implant,
`patients in the 0.7 mg treatment arm required a mean of
`4.1 treatments during the 3-year study, and 22% achieved
`> 15 letters in BCVA gains compared with 12% of patients
`treated with sham." Patients receiving the implant also
`experienced a mean reduction in central retinal thicknessof
`-111.6 um from baseline compared with -41.9 um in patients
`in the sham group.
`However, rates of complications with the 0.7 mg implant
`were high: 68% of phakic patients had cataract-related
`adverse events versus 20% in the sham group, and more
`
`than 40% of treated patients required medication to control
`increasesin IOP versus 9% in the sham group."° In addition,
`recurrence of edema has been reported 16 to 20 weeks after
`treatmentin somepatients.'®
`In clinical trials of the nonbiodegradable intravitreal
`fluocinolone acetonide implant, patients with persistent
`DMEtreated with a high-dose(0.5 pg/day) or low-
`dose (0.2 g/day) implant were more likely to achieve
`a > 15-letter BCVA improvement compared with those
`receiving sham treatment (29% and 28% versus 19%,
`respectively).'7 Approximately 70% to 75% of patients
`required only one treatment during the 3-year study.
`However, amongindividuals who were phakic at baseline,
`87% of high-dose patients required cataract surgery
`compared with 27% in the sham arm. Incisional glaucoma
`surgery was required in 4.8% of low-dose and 8.1% of
`high-dose patients.”
`
`INNOVATIONS IN SUSTAINED RELEASE STEROIDS
`Thefeasibility of using a suprachoroidal route of
`administration is currently being evaluatedin trials of small
`molecules, biotherapeutics, and gene therapies for several
`ophthalmic indications (Figure).
`With suprachoroidal delivery, studies show that the
`choroid, retinal pigment epithelium, and retina are targeted
`with high bioavailability while low levels of therapeutic agent
`are maintained elsewherein the eye (eg, the vitreous or
`anterior chamber).'®"9
`
`Exhibit 2262
`
`Page 02 of 03
`
`SEPTEMBER 2021| RETINA TODAY 35
`
`Exhibit 2262
`Page 02 of 03
`
`

`

`> DIABETIC EYE DISEASE
`
`Suprachoroidal
`
`Intravitreal
`delivery
`
`delivery
`
`antiinflammatory effects, but current
`intravitreal steroids are limited by
`modest longevity and frequent adverse
`events. A novel suprachoroidaldelivery
`option that permitted a yearly dosing
`regimen would be a welcome addition
`to our armamentarium for treatment of
`this growing patient population. =
`
`1. Zheng Y, He M, Congdon N. Theworldwide epidemicof diabetic retinopathy.
`IndianJOphthalmol. 2012:60(5):428-431.
`2. TeoZL, Tham YC, Yan Yu MC,et al. Global prevalence of diabetic retinopathy and
`projection of burden through 2045:systematic review and meta-analysis. Preprint.
`Posted online May 1, 2021. Ophthalmology.
`3. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and majorrisk factors of
`diabetic retinopathy. Diabetes Core. 2012;35(3):556 564.
`4. Petrella RJ, Blouin J, Davies B, Barbeau M. Prevalence, demographics, and
`treatment characteristics of visual impairment due to diabetic macular edema ina
`Tepresentative Canadian cohort. J Ophthalmol. 2012:2012:159167.
`5. Bhagat N. Grigorian RA, Tutela A,Zarbin MA. Diabetic macular edema: pathogen-
`esis and treatment. Surv Ophthalmol. 2009:54(1)+32.
`6. AmoakuWM, Ghanchi F, Bailey C, et al. Diabetic retinopathy and diabetic
`macular oedema pathways and management: UK ConsensusWorking Group.Eye
`(ond). 2020;34(Suppl1):1-51.
`7. Schmidt-Erfurth U, Garcia-Arumi/J, Bandello F, et al. Guidelines for the manage-
`ment of diabetic macular edema by the EuropeanSociety of Retina Specialists
`(EURETINA). Ophthalmalagica. 2017:237(4):185-222.
`§. Neuyen OD, Brown OM, Marcus DM,et al. Ranibizumabfor diabetic macular
`edema: results from 2 phaseIll randomized trials: RISE and RIDE. Ophthalmology.
`2012:119(4):789-801.
`9. Korobelnik JF, Do OV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for
`diabetic macular edema. Ophthalmology. 2014:12i(11):2247-2254.
`10.Wells A, GlassmanAR, AyalaAR,et al.; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab,or
`ranibizumabfor diabetic macular edema. NEngl J Med. 2015:372:1193-203.
`ii. Mitchell P, Sheidow TG, Farah ME, et al. Effectiveness and safety of ranibizumab 0.5 mgin treatment-naive patients with
`diabetic macular edema: Results from the reakworld global LUMINOUS study.PLoS One. 2020:15(6):e0233595.
`12. Roche. Angiogenesis Highlights 2021. February 16, 2021.Accessed June 28, 2021. www.roche.com/damjcr-labc3f66-3d4f-
`4q07-Beb6-2BeB1c?elcc2/en/anglogenesis-2021.pdf
`13. Kodiak Sciences. Kodiak Sciences announces 1-year durability, efficacy and safety data from ongoing phase 1b study of
`KSI-301 in patientswith wet age-related macular degeneration, diabetic macular edemaandretinal vein occlusion at the
`Angiogenesis, Exudation and Degeneration 2021 Annual Meeting [press release]. February 13, 2021. Accessed June 28, 2021.
`ir.kodiakcom/news-releases/news-release-details/kodiak-sclences-announces-1-year-durability-efficacy-and-safety
`14.Whitcup SM, Cidlowski JA, Csaky KG,Ambati J. Pharmacology of corticosteroids for diabetic macular edema. Invest
`Ophthalmal Vis Sci. 2018;59(0):1-12.
`15. Boyer DS, Yoon YH, Belfort RJr, et al. Three-year, randomized, sham-controlledtrial of dexamethasoneintravitreal implant
`in patients with diabetic macular edema. Opithalmalagy. 2014:121(10):19041914,
`16. Mathew R, Pearce E, Muniraju R, Abdel-Hay A, Sivaprasad S. Monthly OCT monitoring of Ozurdex for macular oedema
`related toretinal vascular diseases: re-treatment strategy (OCTOMEReport 1).Eye (Lond). 2014:28(3):319-326.
`17. Campochiaro PA, Brown DM, PearsonA,et al. Sustained delivery fluocinolone acetonidevitreous inserts provide benefit
`for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012:119(10):2125-2132.
`18. Chiang B, Jung JH, Prausnitz MR. The suprachorvidal space as a route of administration to the posterior segment of the
`eye. Adv Drug DelivRev. 2019:126:58-66.
`19.Jung JH, Chae JJ, Prausnitz MR.Targeting drug delivery within the suprachoroidal space. Drug Discov Today.
`2019:24(8)1654-1659.
`20. Oxular Limited. Data onfile, 2021.
`
`Figure. Suprachoroidal drug delivery may target the retina, choroid, and retinal pigment epithelium with high bioavailability.
`
`OXU-001 (Oxular Limited) is a novel sustained-release
`steroid formulation of dexamethasoneincorporated into
`biodegradable microspheres.Injected suprachoroidally, the
`microspheres are designed todeliver a precise daily amount
`of dexamethasoneto retinal and choroidaltissues for up to
`12 months.2°
`A preclinical study of suprachoroidal administration of
`OXU-001 in rabbits found that therapeutic levels of the
`drug were maintained for approximately 1 year.?° Levels of
`steroid in the vitreous and lens throughout the study period
`were low, which the researchers suspect maytranslate into a
`favorable clinical safety profile.
`In the clinic, OXU-001 is delivered using a semiautomated
`ocular administration device with a microcatheter to target
`the posterior suprachoroidal compartment. The catheteris
`injected at the pars plana and automatically deploys posteri-
`orly upon reaching the suprachoroidalspace.Illumination of
`the microcatheter providestransscleral visual confirmation
`of accuratelocation prior to drug delivery.
`The developeris planning a phase 2 randomizedclinical
`study of OXU-001 in patients with DME,to begin later this
`year. The study will compare suprachoroidally administered
`OXU-001 with the dexamethasoneintravitreal implant.
`
`Current anti-VEGF therapies for DMEare effective but
`are associated with high treatment burdensforpatients,
`caregivers, and retina specialists. Corticosteroids can
`provide benefit in DME dueto their antiedematous and
`
`36 RETINA TODAY | SEPTEMBER 2021 Exhibit 2262
`Page 03 of 03
`
`SOBHA SIVAPRASAD, MBBS,MS, DM, FRCS, FRCOPHTH
`= Professor of Retinal Clinical Studies, UCL Institute of Ophthalmology, London,
`United Kingdom
`= Consultant Ophthalmologist, Moorfields Eye Hospital, London, United Kingdom
`m senswathi@aol.com
`m= Financial disclosure: Research Grants (Novartis, Bayer, Allergan, Roche,
`Boehringer Ingelheim, Optos): Travel Grants (Novartis, Bayer); Speaker Fees
`(Novartis, Bayer, Optos): Advisory Board (Novartis, Bayer, Allergan, Roche,
`Boehringer Ingelheim, Optos, Oxurion, Opthea, Apellis, Oculis, Heidelberg
`Engineering)
`
`Exhibit 2262
`Page 03 of 03
`
`