Diabetic Macular Oedema

Transcription

1 ntravitreal LUVE mplant for Diabetic Macular Oedema Early Case Experiences homas Bertelmann 1 and Anke Messerschmidt-Roth 2 1. enior Physician; 2. tudy Co-ordinator, Department of Ophthalmology, Philipps University, Marburg, Germany Abstract Diabetic macular oedema (DMO) is an important cause of vision loss and challenges remain in the treatment of this progressive disease. Corticosteroids provide a comprehensive treatment approach, lowering the concentration of inflammatory cytokines and growth factors such as vascular endothelial growth factor (VEGF). However, intravitreal injections are often short-lived and are associated with intraocular side effects. he LUVE intravitreal implant contains fluocinolone acetonide and is administered by injection into the vitreous cavity. ts efficacy and safety have been demonstrated in clinical studies, and a subgroup analysis has shown that it is particularly beneficial in patients with long-standing DMO a group with poor visual outcomes and limited treatment options. As a result, the LUVE implant has been approved in Europe for the treatment of visual impairment due to chronic DMO considered insufficiently responsive to available therapies. hese data have been supported by real-use clinical experience and two cases are presented that demonstrate the effectiveness of the LUVE implant in two patients where prior therapies including ranibizumab have not produced a sustained beneficial effect. Keywords Corticosteroids, LUVE, fluocinolone acetonide, diabetic macular oedema Disclosure: he authors have no conflicts of interest to declare. Acknowledgements: Editorial assistance was provided by Katrina Mountfort at ouch Medical Media. Received: 24 October 2013 Accepted: 14 ovember 2013 Citation: European Ophthalmic Review, 2013;7(2):122 6 Correspondence: homas Bertelmann, Department of Ophthalmology, Philipps University Marburg, Baldingerstraße, Marburg, Germany. E: thomas.bertelmann@staff.uni-marburg.de upport: he publication of this article was supported by Alimera ciences Ltd. he views and opinions expressed in the article are those of the authors and not necessarily those of Alimera ciences Ltd. Diabetic macular oedema (DMO) is the primary cause of vision loss in diabetic retinopathy (DR), which is the leading cause of blindness in the working population among patients aged 20 to 70 years in developed countries. 1,2 he global prevalence of DR among individuals with diabetes is around 35 %, with DMO present in 6.8 %. 3 he prevalence rates of DR were significantly higher in individuals with type 1 diabetes compared with type 2 (77.3 % versus 25.2 %). 3 he total number of people with diabetes worldwide is projected to rise from 366 million in 2012 to 552 million in 2030, a factor of 1.5 within 20 years. 4 t is anticipated that the annual incidence of diagnosed DMO will increase in line with the increase in diabetes, suggesting that 37.5 million people worldwide will have DMO by 2030, and will represent a substantial global health and economic burden. his article aims to examine the treatment options for DMO and to assess the clinical data in support of the LUVE intravitreal implant, as well as discussing two clinical cases illustrating the use of the LUVE implant. Pathophysiology of Diabetic Macular Oedema DMO is a consequence of persistent hyperglycaemia and, if untreated, results in a rapid decline in visual acuity (VA). 5 he pathophysiology of the condition is a complex process whereby hyperglycaemia initiates molecular pathways leading to dilated capillaries, retinal microaneurysms, and loss of pericytes. 6 his results in impairment of the blood retinal barrier (BRB) and increased vascular permeability, causing fluid to accumulate in retinal tissue. 7 9 At early disease stages, vascular endothelial growth factor (VEGF) is the major driver of retinal changes. However, a large number of physiological and molecular factors, including angiogenesis, inflammation and oxidative stress, are involved in the pathogenesis of DMO n chronic DMO, heightened inflammation is primarily responsible for the perpetuation of retinal changes. 11 Diabetic Macular Oedema reatment Options n addition to tight glycaemic control to reduce glycated haemoglobin (HbA 1c ) levels, prevention of visual loss depends on the timely detection of DMO and immediate initiation of adequate therapy. he severity of DMO is assessed by measuring foveal thickness and the decline in VA. Current treatment options for DMO include laser photocoagulation and the use of intravitreal drugs. Grid macular photocoagulation was the standard of care for over 25 years, 12 but VA gains were only modest. 13,14 Data from clinical studies showed that around 40 % of eyes gained between 0 and 5 letters on the Early reatment Diabetic Retinopathy tudy (EDR) scale over a 2-year period n terms of pharmacological treatment of DMO, ranibizumab (an antiangiogenic agent) was approved by the European Medicines Agency (EMA) in 2011 for the treatment of vision impairment secondary to DMO, after demonstrating improvements in VA and reductions in retinal thickness in clinical trials he Ranibizumab njection in ubjects 122 ouch MEdical MEdia 2013

2 ntravitreal LUVE mplant for Diabetic Macular Oedema Early Case Experiences With Clinically ignificant Macular Edema (RE and RDE) studies evaluated the long-term efficacy and safety of ranibizumab, and data over 36 months have recently been published. 21 Other anti-vegfs with demonstrated efficacy on DMO include bevacizumab 22 and pegaptanib sodium. 23 However, the blockade of one single pathway may not represent an optimum treatment strategy and may explain why some patients need retreating or do not respond sufficiently. Figure 1: LUVE mplant, hown on a Human Finger to ndicate ize Corticosteroids do not only have the capacity to attenuate the effects driven by overexpression of VEGF, but also reduce inflammation, and may provide a more comprehensive treatment strategy in the longterm. 24 Corticosteroids reduce vascular permeability of the retina by a multifactorial process, including lowering the expression of VEGF and suppressing inflammation and leukocyte influx to the retina. he most widely used corticosteroid is triamcinolone acetonide (A), which has shown clinical benefits in various randomised clinical trials for the treatment of DMO, and also shown improvement in VA. 17,25,26 A Diabetic Retinopathy Clinical Research etwork (DRCR) study has shown that pseudophakic eyes have a comparable benefit with A compared with ranibizumab. 12,14,27 However, the use of intravitreal A has been associated with cataracts and increased intraocular pressure (OP). 28 he administration of ocular agents for DMO is problematic. 29 opical administration does not achieve intraocular therapeutic concentrations. 30 he effects of direct intravitreal injections are often short-lived and are associated with serious side effects, including cataract and elevation of OP. Furthermore, repeated intravitreal injections impose a heavy treatment burden on patients and clinical centres and may increase the risks associated with the injection procedure, such as endophthalmitis and retinal breaks. herefore, recent research has focused on the use of intravitreal implants. ustained drug-delivery systems release low doses over a prolonged period, resulting in a stable and sustained intravitreal concentration of the drug thus reducing the number of injections. 31 An intravitreal implant containing dexamethasone is currently in clinical development for the treatment of DMO. 32 Figure 2: nner View of Pars Plana with eedle of Device Releasing the LUVE mplant into the Vitreous Cavity Fluocinolone actetonide (FAc) is an attractive choice for use in intravitreal implants. t is more lipophilic than A and dexamethasone 33 and therefore is expected to have superior posterior clearance with less potential for ocular side effects. 34 he first steroid-containing intravitreal implant (Retisert, not licensed in Europe) released 0.59 µg/day of FAc. A phase study investigating the efficacy and safety of the Retisert FAc implant in 196 eyes with DMO found that VA gains of 15 EDR letters occurred in 16.8 % of implanted eyes at 6 months and 31.1 % of eyes at 3 years compared with 1.4 % at 6 months and 20 % at 3 years in the laser treatment group. 34 he incidence of elevated OP and cataract formation was much higher in eyes receiving the implant: 33.8 % required surgery for ocular hypertension and 91 % required cataract extraction by 4 years compared with 0 % and 20 % in the standard of care group (observation or laser), respectively. 34 he LUVE ntravitreal mplant he LUVE (Alimera ciences) intravitreal implant is a small, cylindrical tube (3.5 mm in length; 0.37 mm in diameter) composed of an inert, non-biodegradable, polyimide material that is often used in the manufacturing of intraocular lenses (see Figure 1). he implant is injected into the vitreous cavity using a 25-gauge (nominal outer diameter mm) applicator, which creates a self-sealing wound (see Figure 2). t is implanted posteriorly and has a lower in vitro FAc release rate compared with Retisert, thus reducing the potential for intraocular side effects. 35 Each implant contains 190 µg of FAc and, after the average initial release of 0.2 µg /day, the implant reaches a steady release that continues for up to 36 months.. 36 When active drug is depleted, the LUVE implant is not retrieved and it remains in the eye. he efficacy and safety of LUVE has been examined in the Pharmacokinetic and Efficacy tudy of Fluocinolone Acetonide mplants in Patients with DMO (FAMOU) and Fluocinolone Acetonide for diabetic Macular Edema (FAME) clinical trials. n the open-label phase (FAMOU) study (n=37), a single implant provided excellent sustained intraocular release of FAc with the 0.2 μg/day FAc insert providing steady-state levels ranging between 0.5 and 1.0 ng/ml from 6 through to 36 months. 36,37 he phase (FAME) clinical trial comprised two randomised, doublemasked, sham injection-controlled, parallel group, multicentre phase trials performed under the same protocol. Eligibility criteria included persistent DMO (central retinal thickness [CR] 250 µm and best-corrected VA (BCVA) score between 19 and 68 despite 1 123

3 Figure 3: FAME tudy Percentage of Patients with 15-letter mprovement in Best-corrected Visual Acuity from Baseline Figure 4: Optical Coherence omography can howing ncreased Foveal hickness in the Right Eye Before and After reatment with the LUVE mplant Before reatment A Full population 28.7 % Before treatment Right eye Left eye B ime (months) Control (n=185) 0.2 μg/d fluocinolone actetonide (n=376) Chronic diabetic macular oedema ( 3 years) 34.0 % wo months after treatment ime (months) Control (n=112) 0.2 μg/d fluocinolone actetonide (n=209) p for difference between 0.2 μg/d FAc insert and sham by Cochran-Mantel- Haenszel chi-square test stratified by baseline best-corrected visual acuity. macular laser treatment. A total of 956 patients were randomised to sham injection (n=185), LUVE implant (0.2 µg/day, n=376) or highdose FAc implant (0.5 µg/day, n=395). At month 36, the percentage of patients who gained 15 EDR letters was 28.7 % (LUVE) and 27.8 % (high-dose FAc) compared with 18.9 % (p=0.018) in the sham group. hese visual gains were paralleled by a decrease in CR. 38,39 he LUVE implant also demonstrated an acceptable safety profile. While most phakic patients in the implant groups developed cataract with the majority undergoing cataract surgery, their visual benefit after surgery was similar to that in pseudophakic patients. 38 he incidence of incisional glaucoma surgery at month 36 was 4.8 % in the LUVE group and 8.1 % in the high-dose FAc groups. Among patients treated with the LUVE implant, 38.4 % required OPlowering medication. 38,39 A preplanned subgroup analysis assessed outcomes in two groups of patients: those with a duration of DMO less than the median (<3 years) or greater than the median ( 3 years) at baseline. his analysis demonstrated a doubling of benefit in patients with chronic DMO. he percentage of chronic DMO patients who gained 15 letters of BCVA or more from baseline at month 36 was 13.4 % in the sham group, 34 % in the LUVE group (p<0.001) and 28.8 % in the high-dose FAc implant group (p=0.002) (see Figure 3). An improvement 2 steps in the ERD retinopathy scale was reported in 13.7 % (LUVE) and 10.1 % (highdose FAc) compared with 8.9 % in the sham group. 38 he findings of the FAME subgroup analysis are of particular significance, given the association between poor visual outcome and disease duration 40 and the limited treatment options for patients with chronic DMO. Based on the evidence reported in the FAME studies, particularly in patients with chronic DMO, LUVE has been approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of visual impairment due to chronic DMO considered insufficiently responsive to available therapies. Clinical Experience wo recent clinical cases of chronic DMO have described the effectiveness and safety of the LUVE implant in real-use situations in chronic DMO considered insufficiently responsive to available therapies. n both cases, the LUVE implant resulted in visual gains and reductions in CR where other therapeutic interventions had failed. Case 1 Medical History he patient was female, aged 71 years, with type 2 diabetes and was diagnosed with DMO on 20 June Her HbA 1c was 8 % and she was receiving insulin therapy. he was pseudophakic in both eyes (OU) since 2009 and has undergone neodymium-doped yttrium aluminum garnet (d:yag) posterior capsulotomy OU. Her BCVA at baseline was 0.4 in the right eye (OD) and 0.7 in the left eye (O). Amsler grid testing was normal O, however, metamorphopsia was documented OD. Figure 4 shows OC scans of both eyes together with the detailed grid for evaluating foveal thickness. he right eye shows DMO with foveal 124

4 ntravitreal LUVE mplant for Diabetic Macular Oedema Early Case Experiences involvement; (central foveal thickness [CF] 448 µm); the left eye shows DMO without foveal involvement (CF 269 µm). Fundus photography on both eyes shows diabetic maculopathy with microaneurysms and intraretinal haemorrhages temporal to the fovea, more profoundly in the left eye (see Figure 5). reatment History he patient received initial treatment with intravitreal bevacizumab in July 2010, which resulted in an improvement in BCVA from 0.4 to 0.5 OD (measured with nellen charts) but CF increased to 480 µm. Following the second injection of bevacizumab 2 months later, a reduction in CF (428 µm) was seen but there was no further visual gain. he treatment was switched to A, which resulted in further reductions in CF (343 µm), but a slight worsening in BCVA (0.4) was observed. he patient was prescribed eye drops (dorzolamide hydrochloride, and timolol, Cosopt ) for a slightly elevated OP (24 mmhg max) in October he patient s OP ranged between 15 mmhg and 23 mmhg at all subsequent followups. Ranibizumab treatment, consisting of five intravitreal injections, was continued from June 2012 until April 2013 (five injections in 11 months or roughly one every 2 months) and resulted in further reductions in CF (368 µm in June 2012, 323 µm in ovember 2012, 342 µm in March 2013 and 314 µm in May 2013, a reduction of 15% in 11 months) but no change in BCVA (0.5 from June 2012 to May 2013). Response to LUVE Due to an insufficient response to ranibizumab therapy, in July 2013, the patient received an LUVE implant. Within 2 months, visual gains were reported (BCVA 0.5 to 0.6), together with a reduction in CF (314 µm to 277 µm, a 12% reduction in 2 weeks). he OC scan taken in eptember 2013 illustrates the improvement in CF (see Figure 4). o date, no adverse events or serious side effects have occurred. he OP at last visit was below 20 mmhg despite the fact that the patient had stopped using Cosopt as prescribed. Case 2 Medical History he second case was a 30 year-old patient with type 1 diabetes who was diagnosed with DMO around 20 years ago. His HbA 1c was 9.5 % and he was receiving insulin therapy. reatment History he patient had undergone panretinal photocoagulation in both eyes, and subsequently had received 25 intravitreal ranibizumab injections OD and 12 O since he OC scan of the left eye taken 4 weeks after the last ranibizumab injection showed severe foveal thickening (CF 642 µm) (see Figure 6). VA testing at this time indicated that the BCVA in this eye was 0.3. Response to LUVE he patient received an LUVE implant on 16 August here was a dramatic improvement in CF O (642 µm to 268 µm, a reduction of 58% in 4 weeks) (see Figure 6) and a 0.2 units improvement in BCVA from 0.3 to weeks later. his improvement was sustained at 12 weeks. Figure 5: Fundus Photography howing Diabetic Maculopathy with Microaneurysms and ntraretinal Haemorrhages (Case 1) Right eye Figure 6: Optical Coherence omography can howing Foveal hickness in the Left Eye Before and After reatment with the LUVE mplant Before treatment Four weeks after treatment Left eye Concluding Remarks DMO is an important cause of vision loss and challenges remain in the treatment of this progressive disease. teroids may reduce the concentration of inflammatory cytokines and growth factors such as VEGF. he efficacy and safety of the LUVE implant has been demonstrated in the FAME clinical studies, and subgroup analysis has shown that the relative benefit was most substantial in patients with chronic DMO. hese data have been supported by real-use clinical experience and suggest that patients with chronic DMO who are unresponsive to current therapies may respond well to the administration of an LUVE implant. n conclusion, the LUVE implant provides an important addition to the treatment options for patients with chronic DMO. n Moss E, Klein R, Klein BE, en-year incidence of visual loss in a diabetic population, Ophthalmology, 1994;101: Klein R, Lee KE, Gangnon RE, et al., he 25-year incidence of visual impairment in type 1 diabetes mellitus the wisconsin epidemiologic study of diabetic retinopathy, Ophthalmology, 2010;117: Yau JW, Rogers L, Kawasaki R, et al., Global prevalence and major risk factors of diabetic retinopathy, Diabetes Care, 2012;35: Culver AL, Ockene, Balasubramanian R, et al., tatin use and risk of diabetes mellitus in postmenopausal women in the Women s Health nitiative, Arch ntern Med, 2012;172: Photocoagulation for diabetic macular edema. Early reatment Diabetic Retinopathy tudy report number 1. Early reatment Diabetic Retinopathy tudy research group, Arch Ophthalmol, 1985;103: Antonetti DA, Lieth E, Barber AJ, et al., Molecular mechanisms of vascular permeability in diabetic retinopathy, emin Ophthalmol, 1999;14: Klaassen, Van oorden CJ, chlingemann RO, Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions, Prog Retin Eye Res, 2013;34: Ehrlich R, Harris A, Ciulla A, et al., Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process, Acta Ophthalmol, 2010;88: Joussen AM, Poulaki V, Le ML, et al., A central role for inflammation in the pathogenesis of diabetic retinopathy, FAEB J, 2004;18:

5 10. Funatsu H, oma H, Mimura, et al., Association of vitreous inflammatory factors with diabetic macular edema, Ophthalmology, 2009;116: ang J, Kern, nflammation in diabetic retinopathy, Prog Retin Eye Res, 2011;30: Diabetic Retinopathy Clinical Research etwork, Elman MJ, Aiello LP, et al., Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema, Ophthalmology, 2010;117: e Heng LZ, Comyn O, Peto, et al., Diabetic retinopathy: pathogenesis, clinical grading, management and future developments, Diabetic Medicine, 2013;30: Diabetic Retinopathy Clinical Research etwork, A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema, Ophthalmology, 2008;115:1447 9, 9 e oheilian M, Garfami KH, Ramezani A, et al., wo-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema, Retina, 2012;32: Arevalo JF, Lasave AF, Wu L, et al., ntravitreal bevacizumab plus grid laser photocoagulation or intravitreal bevacizumab or grid laser photocoagulation for diffuse diabetic macular edema: results of the Pan-american Collaborative Retina tudy Group at 24 months, Retina, 2013;33: Diabetic Retinopathy Clinical Research etwork, Beck RW, Edwards AR, et al., hree-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema, Arch Ophthalmol, 2009;127: Massin P, Bandello F, Garweg JG, et al., afety and efficacy of ranibizumab in diabetic macular edema (REOLVE tudy): a 12-month, randomized, controlled, double-masked, multicenter phase study, Diabetes Care, 2010;33: Mitchell P, Bandello F, chmidt-erfurth U, et al., he REORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema, Ophthalmology, 2011;118: wang H, un X, Liu K, et al., ntravitreal ranibizumab (Lucentis) for the treatment of diabetic macular edema: a systematic review and meta-analysis of randomized clinical control trials, Curr Eye Res, 2012;37: Brown DM, guyen QD, Marcus DM, et al., Long-term Outcomes of Ranibizumab herapy for Diabetic Macular Edema: he 36-Month Results from wo Phase rials: RE and RDE, Ophthalmology, 2013;120: Rajendram R, Fraser-Bell, Kaines A, et al., A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOL) in the management of diabetic macular edema: 24-month data: report 3, Arch Ophthalmol, 2012;130: ultan MB, Zhou D, Loftus J, et al., A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema, Ophthalmology, 2011;118: tewart MW, Corticosteroid use for diabetic macular edema: old fad or new trend?, Curr Diab Rep, 2012;12: Audren F, Lecleire-Collet A, Erginay A, et al., ntravitreal triamcinolone acetonide for diffuse diabetic macular edema: phase 2 trial comparing 4 mg vs 2 mg, Am J Ophthalmol, 2006;142: Gillies MC, utter FK, impson JM, et al., ntravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial, Ophthalmology, 2006;113: Elman MJ, Bressler M, Qin H, et al., Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema, Ophthalmology, 2011;118: Baath J, Ells AL, Crichton A, et al., afety profile of intravitreal triamcinolone acetonide, J Ocul Pharmacol her, 2007;23: Javey G, chwartz G, Flynn HW, Jr., Emerging pharmacotherapies for diabetic macular edema, Exp Diabetes Res, 2012;2012: McGhee C, Dean, Danesh-Meyer H, Locally administered ocular corticosteroids: benefits and risks, Drug af, 2002;25: Lee, Robinson MR, ovel drug delivery systems for retinal diseases. A review, Ophthalmic Res, 2009;41: Pacella E, Vestri AR, Muscella R, et al., Preliminary results of an intravitreal dexamethasone implant (Ozurdex(R)) in patients with persistent diabetic macular edema, Clin Ophthalmol, 2013;7: hakur A, Kadam R, Kompella UB, nfluence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids, Drug Metab Dispos, 2011;39: Pearson PA, Comstock L, p M, et al., Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial, Ophthalmology, 2011;118: Edelhauser HF, Rowe-Rendleman CL, Robinson MR, et al., Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications, nvest Ophthalmol Vis ci, 2010;51: Campochiaro PA, guyen QD, Hafiz G, et al., Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants, Ophthalmology, 2013;120: Campochiaro PA, Hafiz G, hah M, et al., ustained ocular delivery of fluocinolone acetonide by an intravitreal insert, Ophthalmology, 2010;117: e Campochiaro PA, Brown DM, Pearson A, et al., ustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema, Ophthalmology, 2012;119: Campochiaro PA, Brown DM, Pearson A, et al., Longterm benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema, Ophthalmology, 2011;118: e Gardner W, Larsen M, Girach A, et al., Diabetic macular oedema and visual loss: relationship to location, severity and duration, Acta Ophthalmol, 2009;87: