Innovations in Ophthalmic Corticosteroid Delivery

Home , Endophthalmitis, Macular edema, Uveitis

ISSUE 28 Innovations in Ophthalmic Corticosteroid Delivery

MICHAEL J. ALLINGHAM, MD, PHD Long-term control of inflammation has been possible for patients with Novel ophthalmic sustained-release corticosteroid uveitis since the advent of implantable sustained-release corticosteroid delivery systems have become available in recent years devices, beginning in 2005 with Retisert® (fluocinolone acetonide in- and more are in various stages of development. Eyecare travitreal implant) 0.59 mg (Bausch & Lomb, Bridgewater, NJ); how- providers familiar with the properties, indications, and ever, the newfound convenience and efficacy associated with Retisert potential advantages of each are positioned to offer their were accompanied by a substantial risk for serious side effects—mainly patients with chronic inflammatory conditions (or who cataracts and glaucoma—related to long-term anterior segment expo- 1 are undergoing surgery) state-of-the-art inflammation sure. Since then, sustained release devices have become available with control and care. varying pharmacokinetic profiles (eg, including lower overall dose, novel sustained release vehicles and administration methods, and shorter durations of effect) that allow more flexibility in dosing across a range of indications.2-5 Although short-acting (1 to 3 months)3,6,7 and long-act- Even as options expand for patients with chronic inflammato- ing (up to 36 months)4,8 agents are currently available or on the horizon, ry conditions of the eye, there remains a need for novel long-acting, no drug to date offers robust intraocular levels for a medium-length du- sustained-release antiinflammatory technologies—particularly those ration of 6 to 12 months, which is the “sweet spot” for many patients that deliver medicine to the posterior chamber—that are safe, effective, with uveitis, in my opinion. A shorter duration version of a fluocinolone easy to administer, and whose duration of bioactivity align well with acetonide intravitreal implant is in the pipeline and might fill that un- patients’ needs. Sustained-release antiinflammatory medications have met need.9 the potential to reduce the frequency of disease flare-ups (that coincide with subtherapeutic medication levels at the end of short courses of Optimal Pharmacodynamics therapy) and lead to better long-term outcomes. A sustained-release corticosteroid device has the potential to In this article, we review trends in the development of sustained achieve better inflammation control over the long-term for patients release technology, focusing on innovations in posterior chamber with uveitis. Assuming one is satisfied that patients are not experiencing corticosteroid administration. intraocular pressure (IOP) elevations, use of a sustained delivery device could decrease the frequency of office visits, which may benefit patients DRUG DELIVERY TRENDS Optimal Pharmacodynamics See INSIDE for: An ongoing challenge in developing corticosteroid therapies is identifying the optimum dose, potency, and duration to control inflamma- Controlling Inflammation After Corneal Cross-linking tion, and delivering medication in a way that minimizes the potential William B. Trattler, MD side effects associated with cumulative anterior segment exposure.

TARGET AUDIENCE This educational activity is EDITORIAL BOARD / FACULTY ADVISORS Topics in Ocular Antiinflammatories is jointly sponsored intended for opthalmologists and opthalmolo- by Candeo Clinical/Science Communications, LLC, and the University Marguerite B. McDonald, MD, FACS, practices of Florida College of Medicine. This publication is administered by gists in residency of fellowship training. at Opthalmic Consultants of Long Island, and is an independent editorial board and supported by an unrestricted LEARNING OBJECTIVES Upon completion of a clinical professor of opthalmology at the New educational grant from Shire. this activity, participants will be able to: York University School of Medicine. She is also Copyright 2019 Candeoi Clinical/Science Communications, LLC. All an adjunct clinical professor of opthalmology at rights reserved. Neither the University of Florida nor Candeo Clinical/ 1. Differentiate virus-clearing immunity from Science COmmunications, LLC, assumes any responsibility for injury pathologic immune processes. Tulane University Health Sciences Center. or damage to persons or proerty arising from the use of information 2. Discuss current and pipeline agents for the Victor L. Perez, MD, is a professor of opthal- or ideas contained in this publication. treatment of viral infection-related ocular mology at the Duke University School of Medi- inflammatory processes. cine. He is also the director of Duke Eye Center’s CME REVIEWER Ocular Immunology Center and Coular Surface MATTHEW J. GRAY, MD 3. Describe the mechanisms of neuroinflammation Program. Assistant Professor in GON. Department of Opthalmology University of Florida College of Medicine 4. Understand the role of neuroprotective medication in glaucoma treatment.

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Supported by an unrestricted education grant from Shire. TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 28

STATEMENT OF NEED DATE OF ORIGINAL RELEASE July 2019. The control of ocular infl ammation is a critical aspect of Approved for a period of 12 months. medical and surgical ophthalmic practice. Despite their side effects, antiinflammatory drugs are used to treat ACCREDITATION STATEMENT a very wide range of conditions throughout the eye, This activity has been planned and implemented in from ocular surface disease and allergic conjunctivitis to accordance with the accreditation requirements and posterior segment conditions. Use of antiinflammatory policies of the Accreditation Council for Continuing agents is also critical in ocular surgery, contributing Medical Education (ACCME) through the joint greatly to patient comfort and positive outcomes. providership of the University of Florida College of The ocular antiinflammatory landscape is changing as Medicine and Candeo Clinical/Science Communications, research reveals more about the role of infl ammation in LLC. The University of Florida College of Medicine is a range of ocular conditions and as new antiinflammatory accredited by the ACCME to provide continuing medical Figure 1: The pretreatment images (left agents enter the market.1,2 Twenty years ago, for example, education for physicians. the idea of using a topical corticosteroid to treat dry eye side) show petalloid leakage by fluo- and/or allergic conjunctivitis was viewed with alarm; CREDIT DESIGNATION STATEMENT rescein angiography (FA) and cystoid today, it is accepted practice. The University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA intraretinal fluid by optical coherence to- Although corticosteroids and nonsteroidal antiinfl Category 1 Credit™. Physicians should claim only ammatory drugs (NSAIDs) have been the mainstays of the credit commensurate with the extent of their mography (OCT). Following administra- the ocular antiinflammatory armamentarium, a number participation in the activity. tion of intravitreal triescence, FA shows of new agents with novel mechanisms of action (and new ocular drug delivery systems) have come to market or are EDITORIAL BOARD/FACULTY resolution of leakage and the OCT has being made ready for market.3,4 ADVISORS regained a normal foveal contour. As indications expand and change, and as new drugs, Marguerite B. McDonald, MD, FACS, formulations, and delivery systems become available, practices at Ophthalmic Consultants of Long Island, and clinicians require up-to-date protocols for drug selection is a clinical professor of ophthalmology at the New York (Images Courtesy of Dr. Allingham) and use. Such protocols are also needed for routine University School of Medicine. She is also an adjunct (but nevertheless off -label) uses of corticosteroids and clinical professor of ophthalmology at Tulane University NSAIDs because important diff erences in effi cacy, safety, Health Sciences Center. Dr. McDonald is a consultant and tolerability exist between these classes and among for Allergan, Alcon, Bausch + Lomb, BlephEx, FOCUS and doctors. Prior to placing an implant, a formulations within each of these classes.5,6 Laboratories, Shire, and J&J Vision. trial of topical prednisolone or a short acting By putting the latest published evidence into the Victor L. Perez, MD, is a professor of intravitreal corticosteroid (such as Triesence context of current clinical practice, Topics in Ocular ophthalmology at the Duke University School of Antiinflammatories equips ophthalmologists to maintain Medicine. He is also the director of Duke Eye Center’s [triamcinolone acetonide injectable suspen- competencies and narrow gaps between their actual and Ocular Immunology Center and Ocular Surface Program. sion]) 40 mg/mL (Alcon, Ft. Worth, TX), optimal inflammation management practices, across the Dr. Perez is a consultant for Allergan, Shire, EyeGate, and range of clinical situations in which current and novel and careful IOP monitoring may be useful to TopiVert. He is also a stock shareholder for EyeGate. ocular antiinflammatories may be used. Matthew J. Gray, MD, is an assistant professor ensure safety and tolerability. REFERENCES in the Department of Ophthalmology at the University of Florida College of Medicine. He states that in the past 12 There are currently four implantable sus- 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern months, he has not had a financial relationship with any tained-delivery corticosteroid devices avail- for dry eye patients in South Korea: a multicenter study. commercial organization that produces, markets, resells, Korean Journal of Ophthalmology. 2014;28(2):115-21. or distributes healthcare goods or services consumed by able in the US, each with different properties, 2. Ciulla TA, Harris A, McIntyre N, Jonescu Cuypers C. or used on patients relevant to this manuscript. indications, and durations of effect: Retisert Treatment of diabetic macular edema with sustained- release glucocorticoids: intravitreal triamcinolone Michael J. Allingham, MD, PhD is a medical indicated for noninfectious posterior uve- retina specialist and assistant professor of ophthalmology acetonide, dexamethasone implant, and fl uocinolone at Duke Eye Center. He is actively engaged in both clinical itis; Ozurdex® (dexamethasone intravitreal acetonide implant. Expert Opin Pharmacother. 2014;15(7):953-9. and basic research with a goal of identifying novel implant) 0.7 mg (Allergan Inc., Irvine, CA) therapeutic targets for macular diseases, particularly 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging those that manifest macular edema. Dr. Allingham states indicated for retinal vein occlusion, noninfec- therapies for noninfectious uveitis: what may be that he is a consultant for Clearside Biomedical. tious posterior uveitis, and diabetic macular coming to the clinics. J Ophthalmol. 2014;2014:310329. William B. Trattler MD, is a refractive, corneal 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and and cataract eye surgeon at the Center for Excellence in edema (DME); Iluvien® (fluocinolone ace- the OPUS-1 Study Group. Lifi tegrast ophthalmic Eye Care, and volunteer faculty at Florida International tonide intravitreal implant) 0.19 mg (Alimera solution 5.0% for treatment of dry eye disease: results University College of Medicine, Miami, FL. Dr. Trattler has Science, Alpharetta, GA) indicated for DME; of the OPUS-1 phase 3 study. Ophthalmology. 2014 received grant/research support from Bio-Tissue and is Feb;121(2):475-83. a consultant for Bausch + Lomb, Kala Pharmaceuticals, and Yutiq (fluocinolone acetonide intravitreal 5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol Sun Ophthalmics, Eyevance Pharmaceuticals, Novartis, implant) 0.18 mg (EyePoint Pharmaceuticals, etabonate gel 0.5% for postoperative pain and Shire, and Allergan. Dr. Trattler is also on the speakers’ infl ammation after cataract surgery: results of a bureau for Bausch + Lomb, Kala Pharmaceuticals, Sun Watertown, MA) indicated for noninfectious multicenter trial. Clin Ophthalmol. 2012;6:1113-24. Ophthalmics, Eyevance Pharmaceuticals, Shire, and posterior uveitis.2,3,4,8 While Retisert requires 6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt Allergan and is a stock shareholder for Avedro and CXLO. surgery for placement, the latter three are less in clinical practice: our experience vs a meta-analysis DISCLAIMER of the literature. Clin Exp Ophthalmol. 2012;S1:003. invasive in that they can be administered via Participants have an implied responsibility to use the OFF-LABEL USE STATEMENT newly acquired information to enhance patient outcomes intraocular injection in the office and do not and professional development. The information require a trip to the operating room. This work may discuss off -label uses of medications. presented in this activity is not meant to serve as a GENERAL INFORMATION guideline for patient care. Procedures, medications, and In particular, as it is the first injectable im- other courses of diagnosis and treatment discussed or This CME activity is sponsored by the University of Florida suggested in this activity should not be used by clinicians plant indicated for treatment of inflammation College of Medicine and is supported by an unrestricted without evaluation of their patients’ conditions and associated with uveitis that offers a 36-month educational grant from Shire. possible contraindications or dangers in use, applicable The University of Florida College of Medicine manufacturer’s product information, and comparison duration of effect, I look forward to being able designates this activity for a maximum of 1 AMA PRA with recommendations of other authorities. to offer the recently approved Yutiq to certain Category 1 Credit™. There is no fee to participate in this activity. In order to receive CME credit, COMMERCIAL SUPPORTERS patients in my practice, such as those that can participants should read the report, and then take This activity is supported by an unrestricted educational be managed with local corticosteroid therapy the posttest. A score of 80% is required to qualify for grant from Shire. CME credit. Estimated time to complete the activity but who experience repeated flares on short- is 60 minutes. On completion, take the test online at er-term antiinflammatory medications. http://cme.ufl .edu/ed/self-study/toai/ System requirements for this activity are: For PC users: Like the surgically inserted intravitreal Windows® 2000, XP, 2003 Server, or Vista; Internet implant, in-office injectable implants still -in Explorer® 6.0 or newer, or Mozilla® Firefox® 2.0 or newer (JavaScript™ and Java™ enabled). For Mac® users: Mac volve committing patients to several months OS® X 10.4 (Tiger®) or newer; Safari™ 3.0 or newer, to years of corticosteroid exposure and carry Mozilla® Firefox® 2.0 or newer; (JavaScript™ and Java™ enabled). Internet connection required: Cable modem, risks that are not associated with intravitreal DSL, or better. injection of shorter-acting drug crystals; risks

2 OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ include patient discomfort from the injection, and, although incidence is low, migration of the implant from the vitreous to the anterior cham- CORE CONCEPTS ber, endophthalmitis, and risks associated with the need for larger needle size for placement (eg, hypotony, vitreous hemorrhage).1,10 Four sustained-release corticosteroid implants now However, the convenience of in-office injection can provide substantial available, including recently launched Yutiq benefit to the patient and eyecare professional. – Yutiq is indicated for inflammation associated with uveitis, can be placed in-office, lasts up to DRUG PLACEMENT TRENDS: THE 36 months SUPRACHOROIDAL SPACE – Iluvien and Ozurdex are shorter-acting also There is an emerging trend toward identifying new routes of drug injectable implants that can be placed in delivery beyond sub-tenon and intravitreal sites of injection. The su- the office prachoroidal space, a potential space between the sclera and the cho- – Ozurdex uses a bioerodible technology roid, is a new site and route of interest for delivering ophthalmic medications intended for the posterior segment. The interest stems from the hope that a sustained-release agent placed in the suprachoroidal space Unique distribution of suprachoroidal space drug deliv- might achieve durable therapeutic levels in the posterior segment while ery involves high concentrations in retina and choroid reducing exposure to the front of the eye. A possible advantage, there- with minimal exposure of anterior segment structures fore, is a better safety profile (with regard to IOP and cataract development in the case of corticosteroids) compared to intravitreal injection or Premiere suprachoroidal agent CLS-TA met primary topical administration. In theory, endophthalmitis risk might also be endpoints in phase 3 trials decreased with suprachoroidal vs intravitreal injection since the needle – CLS-TA reduced dosing need for Eylea by half tip does not enter the vitreous. However, more real world experience is in patients with DME in phase 2 trial needed before this potential benefit is confirmed. – IOP elevation rates associated with Until recently, the suprachoroidal space has been poorly accessible suprachoroidal CLS-TA similar to placebo by injection. The main obstacle has been that, as a potential space only, ordinary needles (eg, those designed for intravitreal injection) glide Dexycu is a new, single-dose intraocular dexameth- through it en route to the vitreous, giving no indication that the needle asone formulation approved for use at the close of tip has pierced the sclera until it has also passed through to the cho- cataract surgery to prevent postoperative inflammation roid. In response to this challenge, researchers at Clearside Biomedical (Alpharetta, GA) engineered a very sharp, fine (30 gauge) proprietary micro-needle injector device, only 1000 microns in length, and a novel technique that facilitates injection into the suprachoroidal space.7 LEARNING OBJECTIVES Suprachoroidal injection technique involves positioning the needle against the sclera 9 mm posterior to the limbus (a more posterior place- Upon completion of this activity, participants will be ment than ordinary intracameral injections), applying gentle pressure able to: to the plunger (as if trying to dispense the contents), then advancing the needle forward with the plunger engaged. Whilst the needle is pressed Trace evolution of sustained-release corticosteroid de- against the sclera, no medicine can be released; however, once the nee- velopment, including most recently approved devices dle tip clears the sclera and enters the suprachoroidal space, resistance decreases, and the medication is injected. Understand roles of currently available and pipeline Corticosteroid Triamcinolone Acetonide (CLS-TA) sustained-release corticosteroids in clinical practice The leading suprachoroidal pipeline product is corticosteroid triamcinolone acetonide (CLS-TA) (Clearside Biomedical, Alpharetta, GA), primary endpoint was chosen—the proportion of subjects gaining which has completed positive phase 3 trials for the treatment of macular 7 ≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in edema associated with uveitis and a phase 2 study for DME. According best corrected visual acuity (BCVA) at week 24. to the company, the goals of developing CLS-TA included improved efficacy over current therapies, local administration, lower side effects, The primary endpoint was met among 46.9% of CLS-TA-treated 14 lower concentration of drug used, and less frequent administration of patients vs 15.6% of placebo-treated patients (P < 0.001). Improve- drug.11 Preclinical studies of suprachoroidal CLS-TA showed localiza- ment was significant throughout the study starting at week 4 (9.6 vs 1.3 tion of triamcinolone acetonide (TA) principally to the sclera, choroid, change in ETDRS letters from baseline among treated and untreated and retina with limited exposure to the vitreous humor and no TA de- arms, respectively). Mean change in central subfield thickness (CST) tected in the aqueous humor.12 Choroid and retinal drug accumulation was also significantly decreased among treated patients compared with with suprachoroidal placement is 1200% greater than the same drug placebo-treated arms starting at week 4 through week 24 ( 152.6 vs delivered by intravitreal injection.13 -17.9 microns change from baseline among CLS-TA vs placebo-treated patients, respectively; P < 0.001). Resolution of anterior chamber cell CLEARSIDE CLINICAL PROGRAM and flare and vitreous haze were significantly reduced with CLS-TA 14 The phase 3 clinical trial PEACHTREE showed that supracho- treatment. roidal CLS-TA significantly improved vision and macular edema in There were no serious adverse events attributed to study drug. Ad- noninfectious uveitis at all anatomical locations.14 One hundred sixty verse events occurring in >5% of subjects in the CLS-TA arm included patients with uveitis (anterior, intermediate, posterior, or panuveitis) elevated IOP (11.5% vs 15.6% with placebo), eye pain (12.5% vs 4.7%), were enrolled in a double-blind, multicenter trial, randomized to re- and cataract (7.3% vs 6.9% with placebo). ceive either two injections of suprachoroidal CLS-TA (at baseline and TYBEE, a 6-month, phase 2, randomized, controlled trial in treat- week 12) or placebo, and followed for 6 months. Rescue corticosteroid ment-naïve eyes with DME, compared suprachoroidal CLS-TA as an was available for either arm as needed. A highly clinically meaningful

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ OCULAR ANTIINFLAMMATORIES 3 adjunct to anti-vascular endothelial growth factor (VEGF) agent Ey- 1 year duration of effect. Development of locally acting, steroid-spar- lea (intravitreal aflibercept) (Regeneron, Tarrytown, NY) dosed every ing antiinflammatory and immunomodulatory agents would also be 3 months, versus Eylea monotherapy dosed once monthly.15 Rescue a great advance. Eylea was available at months 4 or 5. As research progresses, the potential to use the suprachoroidal space The primary endpoint was the mean change in BCVA from base- for sustained-release medication delivery of diverse molecules—anti- line to week 24. Patients treated with combination therapy experi- angiogenic molecules, anti-VEGF, antivascular leakage medication, enced a mean change in BCVA from baseline to week 24 of 12.3 letters even NSAIDs—might benefit patients with DME, vein occlusion, vs a mean change in BCVA of 13.5 letters with monthly Eylea mono- AMD, among other conditions. Clearside Biomedical lists (a) a propri- therapy (P > 0.05). These data indicate that CLS-TA treatment allowed etary compound for treatment of retinal vascular disease and (b) gene for 50% fewer Eylea injections without significantly compromising therapy for orphan diseases as suprachoridal therapies entering visual outcomes.15 preclinical study.7 A secondary anatomical endpoint, mean change in CST from Michael J. Allingham, MD, PhD is a medical retina specialist and baseline to week 24 was significantly greater in the CLS-TA plus assistant professor of ophthalmology at Duke Eye Center. He is ac- Eylea arm (-226 microns) compared with monthly Eylea monotherapy tively engaged in both clinical and basic research with a goal of iden- (176 microns; P = 0.035), indicating that the inclusion of suprachoroi- tifying novel therapeutic targets for macular diseases, particularly dal CLS-TA in the treatment regimen was associated with better drying those that manifest macular edema. Dr. Allingham states that he is a of the macula. consultant for Clearside Biomedical. Medical writer Noelle Lake, MD These are promising results, and more work needs to be done to assisted in the preparation of this manuscript. specify the role of corticosteroids in the treatment of DME and/or for REFERENCES whom combination therapy holds a real advantage. Of note, these stud- 1. de Oliveira Dias JR, Nunes RP, Goldhardt R. New drugs and new posterior ies report on findings of two suprachoroidal injections spaced 3 months delivery methods in CME. Curr Ophthalmol Rep. 2017;5:160-8. apart. Assuming suprachoroidal CLS-TA becomes approved, the side 2. Iluvien Prescribing Information 2014. Almira Pharmaceuticals, Inc. effects and real-world tolerability of repeated injections in the supracho- Alpharetta, GA. roidal space would remain to be seen. 3. Ozurdex Prescribing Information 2018. Allergan USA, Inc. Madison, NJ. POSTOPERATIVE TRENDS: DEXAMETHASONE 4. Yutiq Prescribing Information 2018. EyePoint Pharmaceuticals. Water- town, MA. Dexycu (dexamethasone intraocular suspension) 9% (EyePoint 5. DEXYCU Prescribing Information 2018. EyePoint Pharmaceuticals, Pharma, Watertown, MA) is a newly available, preservative-free, Watertown, MA. long-acting corticosteroid formulation indicated for treatment of post- Prescribing Information operative inflammation.5 Dexycu, which contains dexamethasone 51.7 6. Triesence 2014. Alcon. Ft. Worth, TX. mg in a proprietary, biodegradable liquid drug delivery vehicle called 7. Clearside Biomedical. Clearsidebio.com. Accessed March 20, 2019. Verisome, is injected into the posterior chamber as a single 0.005 mL 8. Retisert Prescribing Information 2018. Allergan USA, Inc. Madison, NJ. dose at the end of cataract surgery, and medication is released over about 9. EyePoint Pharmaceuticals. https://eyepointpharma.com. Accessed March 21 days.5,9 20, 2019. As efforts to simplify postoperative regimens are gaining traction, 10. Shah KK, Majumder PT, Biswas J. Intravitreal therapeutic agents in noninfectious uveitic macular edema. Indian J Ophthalmol. and patients, particularly those who opt for premium lenses, would like- 2018;66:1060-73. ly welcome the convenience of “dropless surgery” afforded in part by 11. Kurup S, Hooten C, Stewart M, et al. Suprachoroidal Drug Administra- a sustained-release antiinflammatory agent. Administration of Dexycu tion. ASRS 2014. Accessed March 20, 2019. Available at https://www. at the end of cataract surgery should reduce or eliminate the need for clearsidebio.com/pdf/ASRS-2016-Kurup-Phase-1-2-and-Phase-2- corticosteroid drops following surgery or, if combined with an intraca- Uveitis-case-studies.pdf meral antibiotic, a need for any postsurgical topical medication. 12. Edelhauser HF, Verhoeven RS, Burke B, et al. Intraocular distribution and targeting of triamcinolone acetonide suspension administered into the Patients at increased risk for postoperative cystoid macular edema— suprachoroidal space. ARVO Meeting Abstracts 2014; 5259-C0055. Ac- including those with comorbid conditions such as epiretinal membrane cessed March 20, 2019. Available at https://iovs.arvojournals.org/arti- or uveitis, or surgical complications such as a ruptured capsule or high cle.aspx?articleid=2270851&resultClick=1 phaco energy requirement—are also particularly good candidates for 13. Shah M. Development and clinical experience with suprachoroidal injec- Dexycu administration at the end of surgery, since in such cases, treat- tion of pharmacodynamics triamcinolone acetonide (CLS-TA) as a local ment at the site of inflammation is especially critical. treatment for noninfectious uveitis. ARVO 2017. Accessed March 20, 2019. Available at https://www.clearsidebio.com/pdf/Shah_2017_ARVO.pdf A summary of Dexycu clinical trial results was recently presented in 14. Yeh S, 2017. Suprachoroidal CLS-TA improves visual acuity and macular Issue 26 of Topics in Ocular Antiinflammatories. edema in noninfectious uveitis: results of the phase 3 PEACHTREE study. Insert link to Candeo TOAI Issue 26 Accessed March 20, 2019. Available at https://www.clearsidebio.com/ pdf/Yeh_PEACHTREE_MAGNOLIA_MacSoc_2019_FINAL_ FUTURE DIRECTIONS AND UNMET NEEDS for_Website.pdf 15. Wykoff C, 2019. Suprachoroidal CLS-TA plus aflibercept compared to -af In the implant category, I believe bioerodible technology will likely libercept monotherapy for DME: results of the randomized phase 2 TYBEE come to predominate for sustained-release drugs, especially for indica- trial. Accessed March 20, 2019. Available at https://www.clearsidebio. tions like wet age-related macular degeneration (AMD) that require com/pdf/Wykoff_TYBEE_MacSoc_2019_FINAL_for_Website.pdf long term treatment. Agents such as Ozurdex that are formulated with a bioerodible vehicle leave no residual shell or vehicle once the dose is fully released. By contrast, nonbioerodible delivery technology as used in Yutiq, Iluvien, and Retisert leave a part of the vehicle in the eye.1,4 Consequences of a nonbioerodible delivery mechanism are unknown; in theory, they might impart a limit to repeated use. As mentioned, there remain a number of unmet needs for sustained-release corticosteroid agents, including agents with 6 month to

4 OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Controlling Inflammation After Corneal Cross-linking

WILLIAM B. TRATTLER, MD progressive keratoconus and post-LASIK ectasia in adults. It can be While corneal collagen cross-linking (CXL) using the used off-label with laser vision correction procedures, intrastromal epithelial-off method (Dresden protocol) is currently ring implantation, thermokeratoplasty procedures and, more recent- FDA-approved for the treatment of progressive ly, to treat infectious keratitis.6 The topical ophthalmic photosensi- keratoconus and post-laser in situ keratomileusis (LASIK) tizer solutions used in CXL are 1) riboflavin 59-phosphate in 20% ectasia, the procedure is not without complications. dextran ophthalmic solution 0.146% (Photrexa Viscous®, Avedro Inc, Post-surgical inflammation causing corneal haze and Waltham, MA), which is FDA-approved for use in all CXL proce- infectious keratitis leading to corneal scarring can occur dures, and 2) riboflavin 59-phosphate ophthalmic solution 0.146% if early management strategies are not implemented. By (Photrexa®, Avedro Inc, Waltham, MA), which is FDA-approved for increasing awareness of the possible complications and use when the corneal stroma is thinner than 400 mm after comple- administering appropriate pre- and postoperative care, tion of the Photrexa Viscous® induction period.6 The KXL system irradiates target tissue with UVA radiation for 30 minutes at 3 mW/ such events may be mitigated and optimal outcomes cm2 via operator alignment of lasers and self-calibration of UVA ir- achieved for patients. radiation intensity. POTENTIAL COMPLICATIONS OF CORNEAL COLLAGEN Corneal collagen cross-linking (CXL) is a procedure used most CROSS-LINKING commonly for the treatment of progressive keratoconus and post-la- The epithelium-off CXL technique is often associated with sig- ser in situ keratomileusis (LASIK) ectasia in adults. Affecting ap- nificant postoperative pain, and visual recovery can be gradual. Per- proximately 0.9% to 3.3% of individuals, with a higher prevalence in haps of more significance are the potential consequences of inflam- individuals of South East Asian and Indian ethnicity, keratoconus is mation, including corneal haze, corneal scarring, infectious keratitis, a corneal ectatic disease characterized by progressive focal thinning sterile infiltrates, delayed epithelial healing, corneal perforation, and irregular astigmatism.1 The condition may lead to reduced visual photophobia, failure of treatment, excessive corneal flattening with acuity and, if severe, the need for a corneal transplant.2 Post-LASIK a hyperopic shift, and endothelial failure. These complications, while ectasia is characterized by compromised integrity of the corneal possible, are not typically observed following the epithelial-on meth- strength following LASIK surgery. It can present from months to od. Further, long-term studies show that progression of keratoconus many years to even more than a decade following LASIK. For both after CXL may occur in 3 to 8% of cases.4,7,8 conditions, most treatments focus on strengthening corneal struc- ture and integrity. TECHNIQUES OF CORNEAL COLLAGEN CROSS-LINKING The procedure of riboflavin/ultraviolet A (UVA)-induced CXL was first reported in a clinical study in 2003.3 The procedure involves the production of reactive oxygen species from the interaction of the photosensitizing agent riboflavin with UV-A light, which results in the formation of chemical bonds within the corneal stroma and sub- sequent mechanical stiffening of the cornea. Microstructural changes include increased collagen fiber diameter, keratocyte apoptosis, resistance to thermal shrinkage, changes in corneal swelling properties, and increased resistance to collagenous degradation.3,4 There are two CXL methods: the epithelial-off method (Dres- den protocol) in which an 8 mm to 9 mm zone of corneal epithelium is debrided followed by the instillation of riboflavin eyedrops/ UV-A application; and the investigational epithelial-on method, in which the epithelium remains intact with the addition of riboflavin Figure 1: Representative slit lamp biomicroscopy image of eyedrops. The latter technique avoids postoperative complications clinical haze after CXL (original magnification x16). associated with epithelial healing of debrided corneal tissue. The epithelial-off method is the only FDA-approved option. The epithelial-on method is still under investigation in separate multicenter clin- Republished from: Greenstein SA, Fry KL, Bhatt J, Hersh PS. ical trials conducted by both Avedro and CXLO. Worldwide, other Natural history of corneal haze after collagen cross-linking studies of the epi-on technique are being undertaken using modified for keratoconus and corneal ectasia: Scheimpflug and riboflavin formulations to enhance penetration through the intact, biomicroscopic analysis. J Cataract Refract Surg. 2010;36:2105-14. hydrophobic corneal epithelium, and by using iontophoresis.5 Copyright © 2010 Elsevier The KXL system was Food and Drug Administration (FDA) approved in 2016 (Avedro Inc, Waltham, MA) for the treatment of

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ OCULAR ANTIINFLAMMATORIES 5 Slit-lamp observations suggest that more than 90% of cases post- CORE CONCEPTS CXL will show corneal haze, with a greater tendency in patients who have more advanced keratoconus (Figure 1). One randomized, con- Corneal collagen cross-linking is indicated for trolled trial investigated the natural history of stromal haze in pa- the treatment of progressive keratoconus and post- tients with keratoconus or ectasia using Scheimpflug densitometry as LASIK ectasia. an objective measure of haze versus subjective physician-determined slit lamp-assessed haze. The study confirmed that, relative to baseline haze (14.9 ± 1.9), there was a significant increase in postopera- There are two CXL procedures: the epithelial-off tive haze at 1 month (23.4 ± 4.4) that plateaued at 3 months (22.4 method (Dresden protocol) which is currently FDA ± 4.8; (P < 0.001) and then decreased at 6 months (19.4 ± 4.8) and approved, and the epithelial-on method which is 12 months (17.0 ± 3.8) using Scheimpflug densitometry (P < 0.01), still investigational. which was not different to the results based on slit-lamp observation. Further, there was significant remnant haze at 12 months in the ker- The invasive epithelial-off CXL method may lead to atoconus group compared to the ectasia group.4 Prior to treatment, as the development of post-procedural complications measured by quantitative real-time polymerase chain reaction (PCR) that require immediate attention to ensure rapid on RNA isolated from tissue debridement, the epithelium and stro- epithelial healing. ma from the cone apex of patients with keratoconus show charac- teristically elevated levels of the inflammatory factors TNF-a, IL-6, Post-operative inflammation can be treated effectively and matrix metalloproteinase 9 (MMP-9) but reduced lysyl oxidase with topical steroids, although IOP elevation is difficult (LOX), which crosslinks collagen and elastin into insoluble fibres, to assess in patients with keratoconus. NSAIDS may be and collagen IVA1.9 Thus, pre- and postoperative consideration of useful to address post-surgical pain. inflammation is important. The occurrence of infectious keratitis after epithelial-off CXL is It is important to manage pre-existing conditions rare. Nonetheless, this severe complication can lead to melting of the such as dry eye and blepharitis in patients prior to cornea or scarring with irreversible visual acuity loss, requiring ker- performing CXL. atoplasty. Symptoms of redness, decreased vision, and pain can develop, and corneal infiltrates can appear shortly after the procedure prior to the epithelial defect healing. Differential diagnosis includes LEARNING OBJECTIVES peripheral sterile infiltrates due to enhanced cell-mediated immunity to staphylococcal antigens at a high concentration in the area of Upon completion of this CME activity, participants will tear pooling.6 be able to: Another complication that may arise following epithelial-off CXL for post-LASIK ectasia is diffuse lamellar keratitis (DLK), a Describe the clinical indications suitable for epitheli- condition in which inflammatory cells accumulate in the flap -in al-off CXL and possible complications that may arise terface.10 While rare, the relatively recent (2016) FDA-approval of from the procedure. the KLX system (Avedro Inc, Waltham, MA) for the treatment of post-LASIK ectasia may see an increased incidence of DLK. Since Pre- and postoperative management strategies for the condition can present with corneal edema and corneal inflamma- potential risk factors and inflammatory and infectious tion, findings similar to other conditions, it is important to ensure complications following epithelial-off CXL. that DLK is not overlooked and untreated in the early post-CXL period.10 effective management of haze, the more potent prednisolone or di- MANAGEMENT OF POSTOPERATIVE INFLAMMATION fluprednate may be preferred. Recent advances in loteprednol for- The primary goal of the treating physician post-CXL should mulations – Inveltys (Kala) and Lotemax SM (B&L) – may allow the be to optimize epithelial healing as quickly as possible, specifically use of a potent topical steroid with a lower risk of IOP elevation in within 3 to 5 days, although healing may take longer in patients with patients requiring extended therapy for corneal haze. irregular, steep corneas and those who have apical scars. A typical An important consideration when managing post-CXL inflam- postoperative approach is to administer topical steroid eyedrops four mation with steroids in keratoconus patients is the thin and flexible times a day for the first week post-CXL and, once the epithelium has nature of the cone-like cornea, which may present difficulty when healed, continue the drops for 1 to 4 weeks to suppress inflammation assessing IOP. These patients often measure low IOP measurements or longer if signs of haze or inflammation persist. Topical steroids regardless of the actual pressure in the eye and, as such, it may be may also be required if haze develops much later in the postoperative difficult to assess accurately the steroid response. Minimizing the fre- period. Since pain is common with the epithelial-off CXL proce- quency and strength of steroids when possible will attenuate severe dure, a nonsteroidal anti-inflammatory drug (NSAID) eyedrop may IOP spikes in these patients. be administered in conjunction with the steroidal eyedrops in the first few days post-procedure. MANAGEMENT OF POSTOPERATIVE INFECTION Generally, any steroidal eyedrop is effective for controlling in- For the treatment of infectious keratitis arising post-CXL sur- flammation, including generic prednisolone acetate, loteprednol gery, identification of the pathogenic agent is important so that the (Lotemax Gel®, Bausch+Lomb, Bridgewater, NJ) and difluprednate infection may be treated effectively. Studies have shown that infec- (Durezol®, Alcon, Fort Worth, TX). Where there may exist a con- tion is predominantly due to gram-positive bacteria (Staphylococcus cern regarding elevated intraocular pressure (IOP) for a patient, a epidermidis, Staphylococcus aureus, Streptococcus salivarius, and lighter steroid such as loteprednol may be advantageous. For more Streptococcus oralis) and less frequently to gram-negative bacteria

6 OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ (Escherichia coli and the virulent Pseudomonas aeruginosa).6 Since Pharmaceuticals, Shire, and Allergan and is a stock sharehold- UVA irradiation kills both bacteria and fungi, it is more likely that er for Avedro and CXLO. Medical writer Caroline Markey PhD of contact with a pathogenic agent occurs during the early postopera- Markey Medical Consulting Pty Ltd assisted in the preparation of tive period rather than during surgery by factors such as the epithe- this manuscript. lial defect, topical anesthetics, use of a soft bandage contact lens, and topical anti-inflammatory medications.6 REFERENCES 1. Gordon-Shaag A, Millodot M, Shneor E, Liu Y. The genetic and envi- Bacterial keratitis may be treated with topical monotherapy (eg, ronmental factors for keratoconus. Bio Med Res Int. 2015;2015:795738. fluoroquinolone) in cases where small, superficial infiltrates are ob- 2. Zadnik K, Barr JT, Edrington TB, et al. Baseline findings in the Collab- served, while larger and/or nonresponsive infiltrates should be treat- orative Longitudinal Evaluation of Keratoconus (CLEK) study. Invest ed more aggressively (eg, fortified tobramycin 13.6 mg/mL/topical Ophthalmol Vis Sci. 1998;39:2537-46. vancomycin 25 mg/mL). Fungal keratitis and Acanthamoeba kerati- 3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced col- tis should be considered in patients in high risk geographic areas and lagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. who are non-responsive to antibacterial medications. For patients 2003;135(5):620-7. with a history of herpetic corneal disease, systemic antiviral prophy- 4. Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal laxis prior to epithelial-off CXL should be considered.6 haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. OTHER PERIOPERATIVE CONSIDERATIONS: DRY EYE 2010; 36:2105-14. AND BLEPHARITIS 5. Lim L, Lim EWL. A review of corneal collagen cross-linking—current trends in practice applications. Open Ophthalmol J. 2018;12(Suppl-1, The most important consideration when performing epitheli- M7): 181-213. al-off CXL is to optimize epithelial healing post-procedure to ensure 6. Belin MW, Lim L, Rajpal RK, Hafezi F, Gomes JAP, Cochener B. Cor- full recovery of the cornea. To this end, it is critical to identify and neal cross-linking: current USA status: report from the Cornea Society. address any pre-existing eye conditions or risk factors prior to sur- Cornea 2018;37(10):1218-25. gery that may impact that healing process and influence the local 7. Koppen C, Vryghem JC, Gobin L, Tassignon M-J. Keratitis and corneal inflammatory response to surgery. One such condition is dry eye, scarring after UVA/riboflavin cross-linking for keratoconus. J Refract as it has the potential to impact negatively epithelial healing. While Surg. 2009;25:S819-S823. CXL outcomes in patients with pre-existing dry eye are shown to be 8. Antoun J, Slim E, El Hachem R, et al. Rate of corneal collagen crosslink- positive,11 the use of punctal plugs to raise the tear film or an amni- ing redo in private practice: risk factors and safety. J Ophthalmol. 2015. otic graft such as Prokera® (Bio-Tissue® Inc., Miami, FL) to enhance 9. Pahuja N, Kumar NR, Shroff R, et al. Differential molecular expres- corneal nerve density/sensitivity and reduce dry eye symptoms are sion of extracellular matrix and inflammatory genes at the corneal cone effective in facilitating epithelial healing.12,13 apex drives focal weakening in keratoconus. Invest Ophthalmol Vis Sci. 2016;57(13):5372-82. Blepharitis and vernal conjunctivitis are other conditions that 10. Mannschreck DB, Rubinfeld RS, Soibermana US, Juna AS. Diffuse require attention prior to performing epithelial-off CXL. Chronic lamellar keratitis after epi-off corneal crosslinking: An underrecognized ocular exposure to bacteria, such as that observed with blepharitis, complication? Am J Ophthalmol Case Reports. 2019; 13:140-42. has the potential to exacerbate host defence mechanisms and activate 11. Taneri S, Oehler S, Asimellis G, Kanellopoulos AJ. Influence of corneal inflammatory processes, which may lead to sterile infiltrate produc- cross-linking for keratoconus on several objective parameters of dry eye. tion and bacterial keratitis following CXL, although more studies J Refract Surg. 2013;29(9):612-6. are required.14 To prevent post-procedural complications, the use of 12. Yellepeddi VK, Sheshala R, McMillan H, et al. Punctal plug: a medical prophylactic antibiotics is advisable. In contrast, the use of NSAIDs device to treat dry eye syndrome and for sustained drug delivery to the eye. 2015; 20(7):884-9. has been shown to increase the risk of patients developing sterile in- Drug Discov Today. filtrates four-fold following epithelial-off CXL.14 13. McDonald MB, Sheha H, Tighe S, et al. Treatment outcomes in the Dry eye amniotic Membrane (DreaM) study. Clin Ophthalmol. CONCLUSION 2018;12:677–81. 14. Cerman E, Ozcan DO, Toker E. Sterile corneal infiltrates after corne- Epithelial-off CXL has had a significant positive impact on the al collagen cross-linking: evaluation of risk factors. Acta Ophthalmol. prognosis of keratoconus, post-LASIK ectasia, and other conditions 2017;95:199-204. in which corneal integrity is compromised. In the absence of imple- menting pre-operative strategies to mitigate risk factors predicting poor outcomes or giving attention to inflammation and infection in the immediate postoperative phase of epithelial healing, epithelial-off CXL can lead to serious complications. Continued research into customized CXL techniques and riboflavin formulations (more so for the less invasive procedure of epithelial-on CXL) will enhance the safety and long-term benefits of this important therapeutic option and expand its application to new indications such as infectious keratitis and corneal ectasia. William B. Trattler MD, is a refractive, corneal and cataract eye surgeon at the Center for Excellence in Eye Care, and volunteer faculty at Florida International University College of Medicine, Miami, FL. Dr. Trattler has received grant/research support from Bio-Tissue and is a consultant for Bausch + Lomb, Kala Pharma- ceuticals, Sun Ophthalmics, Eyevance Pharmaceuticals, Novartis, Shire, and Allergan. Dr. Trattler is also on the speakers’ bureau for Bausch + Lomb, Kala Pharmaceuticals, Sun Ophthalmics, Eyevance

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ OCULAR ANTIINFLAMMATORIES 7 EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 28

This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire. Participants must score at least 80% on this exam in order to receive credit. The University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. To take this exam and obtain credit, please take the test online at http://cme.ufl.edu/ed/self-study/toai/. Expires June 30, 2020

1. Which management strategies for post- 5. Which duration of effect is currently 9. Which of the following corticosteroid CXL inflammation are recommended? NOT available from a sustained release implants is NOT placed via an in-office corticosteroid available in the US? procedure? A. Topical steroidal eyedrops administered for only 5 days after A. 3 weeks A. Iluvien Epi-Off CXL B. 1 to 3 months B. Yutiq B. High potency steroidal eyedrops C. 6 to 12 months C. Ozurdex administered every hour for keratoconus patients D. 2 to 3 years D. All of the above can be placed via an in-office procedure C. Topical steroidal eyedrops and 6. Which statements are correct regarding NSAIDs if indicated for pain post-CXL infectious keratitis: 10. Corneal collagen cross-linking is D. Topical NSAID applied QID for 2-3 FDA-approved for which clinical weeks following Epi-Off CXL A. Infection is predominantly due to presentations: gram-negative bacteria 2. Which of the following is true regarding B. Small superficial infiltrates outside A. Post-LASIK ectasia and stable suprachoroidal CLS-TA dosed once every of the visual axis should be treated keratoconus 3 months in clinical trials? aggressively with fortified B. Pellucid Marginal Degeneration and tobramycin/vancomycin progressive keratoconus A. Improved visual acuity at 24 weeks in uveitis patients C. Pathogen identification is not C. Infectious keratitis and stable critical to achieving optimal infection keratoconus B. Reduced central subfield thickness at control when there is a large central D. Post-LASIK ectasia and progressive week 24 in uveitis and, as adjunct to corneal ulcer Eylea, in DME patients keratoconus D. Infection is predominantly due to C. Both A and B gram-positive bacteria D. None of the above 7. Which peri-operative management 3. Which of the following statements is strategies are relevant for accurate regarding the newly approved epithelial-off CXL: product Dexycu (dexamethasone intraocular suspension) 9%? A. Use of an amniotic graft such as PROKERA to help close a persistent A. It contains triamcinolone epithelial defect B. It is preservative-free B. Use of prophylactic antibiotics for C. It is indicated for chronic inflamma- treatment of blepharitis prior to CXL tion associated with DME C. Use of punctal plugs to raise the tear D. It is formulated for periocular film for dry eye injection D. All of the above

4. Technique for injecting medication into 8. Corneal haze and infectious keratitis may the suprachoroidal space result from which procedure:

A. Requires patients be placed under A. Epithelial-off CXL for general anesthesia post-LASIK ectasia B. Requires a proprietary micro-needle/ B. Epithelial-on CXL injector system C. Dresden protocol CXL for C. Involves aspirating suprachoroidal keratoconus fluid once the needle pierces the sclera D. All of the above D. Increases patient risk for hypotony because a large gauge needle is used

8 OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/