Dexamethasone posterior segment drug delivery system (Ozurdex) for diabetic macular oedema

Transcription

1 Dexamethasone posterior segment drug delivery system (Ozurdex) for diabetic macular oedema This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The NIHR Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Dexamethasone posterior segment drug delivery system (Ozurdex) for diabetic macular oedema Target group Diabetic macular oedema (DMO) first or second line. Background DMO is a common complication associated with diabetic retinopathy, and the most common cause of visual impairment in diabetes mellitus 1. It occurs mainly as a result of disruption to the blood-retinal barrier, leading to increased vascular permeability and the accumulation of fluid within the intraretinal layers of the macula 1. Macular oedema (MO) is classified as either diffuse or focal: diffuse MO is a generalised thickening caused by extensive capillary dilation or capillary closure while focal MO is associated with a leaking microaneurysm 1,2. Hypoxia, due to vasoconstriction and capillary loss, upregulates the expression of vasoproliferative factors such as vascular endothelial growth factor (VEGF) and pro-inflammatory mediators such as interleukin-6 in DMO 1,3. Clinically significant macular oedema (CSMO) occurs where there is a threat to central vision and may be defined as 1,2 : thickening of the retina at or within 500µm of the centre of the macula, and/or hard exudates at or within 500µm of the centre of the macula with thickening of the adjacent retina, and/or zone(s) of retinal thickening one disc area or larger, any part of which is within one disc diameter of the centre of the macula. Technology description Dexamethasone posterior segment drug delivery system (DEX PS DDS, Ozurdex) is an implant injected into the vitreous that delivers dexamethasone to the posterior segment of the eye. Corticosteroids have been shown to inhibit the expression of VEGF and other pro-inflammatory mediators 4. Dexamethasone is a potent corticosteroid and suppresses inflammation by inhibiting oedema, fibrin deposits, capillary leakage and phagocytic migration 5. Ozurdex allows sustained delivery of dexamethasone to the vitreous cavity and retina. The implant is made of a solid biodegradable polymer which enables dualphase pharmacokinetics, initially releasing a burst of dexamethasone to rapidly achieve a therapeutic concentration followed by a lower sustained release 6. It is administered by intravitreal (IVT) injection of either a 350µg or 700µg implant. Patients can receive a maximum of 7 implants over a 39 month period, with a minimum 6-month interval between treatments. Ozurdex is licensed for the treatment of adult patients with MO following branch retinal vein occlusion or central retinal vein occlusion, and for inflammation of the posterior segment of the eye presenting as non-infectious uveitis 5. The most common adverse events (AEs) associated with Ozurdex include increased intraocular pressure (IOP), retinal detachment, vitreous detachment, vitreous opacities, myodesopsia, visual disturbance, visual impairment, cataract, blepharitis, eyelid pruritis, headache and migraine 5. Innovation and/or advantages If licensed, Ozurdex may provide long-lasting improvement in VA without the need for regular injections associated with current anti-vegf treatments. 2

3 Developer Allergan. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to The NHS Outcomes Framework ( ) and The National Service Framework for Diabetes (2003). Relevant guidance NICE technology appraisal in development. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema. Expected November NICE technology appraisal. Dexamethasone intravitreal implant for the treatment of 8 macular oedema secondary to retinal vein occlusion NICE technology appraisal. Ranibizumab for the treatment of diabetic macular 9 oedema NICE quality standard for diabetes NICE clinical guideline. Type 2 diabetes: the management of type 2 diabetes 11 (update) NICE clinical guideline. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults Scottish Medicines Consortium. Advice on ranibizumab for the treatment of visual impairment due to diabetic macular oedema in adults SIGN. Management of diabetes The North East Treatment Advisory Group. NETAG appraisal and recommendation: 15 Bevacizumab or ranibizumab (Lucentis) for diabetic macular oedema Royal College of Ophthalmologists. Guidelines for Intravitreal Injections Procedure Royal College of Ophthalmologists. Guidelines for diabetic retinopathy Clinical need and burden of disease In 2010, the number of people diagnosed with diabetes in England and Wales was 2.34 million 17. Approximately 7% of people with diabetes have DMO, 39% of whom are estimated to have CSMO 17. The prevalence of DMO increases to 29% in patients who use insulin for more than 20 years and 27% of patients are thought to develop DMO within 9 years of type 1 diabetes onset 1,18. The prevalence of DMO is related to the duration and severity of diabetes, older age, the presence of hypertension, nephropathy (kidney disease), pregnancy, smoking, obesity, having a high cholesterol level, and for type 2 diabetes, by the clinical need for insulin therapy 1,2,18,19. The prevalence of DMO is also reportedly higher in African (15.2%) and black Caribbean (14.7%) when compared with white ethnic groups (9.4%) 20,b. The 10-year incidence of DMO in those diagnosed before 30 years of age (younger onset) is 20.1%, but is higher at 39.3% for those diagnosed from 30 years of age onward (older onset) 1. In addition, those with older onset disease tend to develop DMO after a shorter time, with a reported prevalence of 3-8% within 3 years compared to 0.5% within 10 years for those with younger onset 1. Untreated DMO has a 25-30% risk of developing in to CSMO 17. If left untreated, up to 33% of eyes with DMO experience moderate vision loss (loss of 15 letters, or 3 lines on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity [VA] chart); 24% of those with CSMO experience this level of vision loss within 2 years 18,21. Visual loss 3

4 from diabetic retinopathy, principally resulting from CSMO, is regarded as the commonest cause of visual impairment in the working population of the Western world 22,a. Screening and early treatment, however, has reduced the incidence of blindness due to diabetes. A recent study from Newcastle, where organised screening for retinopathy started in 1986, reported that diabetes was no longer the commonest cause of blindness in the working age population 21. Existing comparators and treatments The current standard of care for sight threatening DMO is focal laser photocoagulation or grid photocoagulation 23. Good management of diabetes and other risk factors, including diet modification, blood pressure control and pharmacological treatments, may delay progression of DMO. Other treatment options for DMO include 18,14,21 : Intravitreal steroids: o Fluocinolone acetonide intravitreal implant alone or in combination with laser photocoagulation (subject to ongoing NICE appraisal) 7. o Intravitreal triamcinolone (Kenalog) for laser-refractory DMO (unlicensed for this indication) 14,22 occasionally used at time of cataract surgery a. Intravitreal anti-vegf agents: o Ranibizumab either as monotherapy or in combination with laser photocoagulation (not currently recommended by NICE) 9. o Bevacizumab either as monotherapy or in combination with laser photocoagulation (unlicensed for this indication) 15 used for cases refractory to laser treatment a. o Pegaptanib (unlicensed for this indication) 22 rarely used a. Vitrectomy used for DMO with vitreo-macular traction or epiretinal membrane a. Efficacy and safety Trial NCT , ; dexamethasone posterior segment drug delivery system (DEX PS DDS) 350μg, 700μg or placebo; phase III. NCT , ; DEX PS DDS 350μg, 700μg or placebo; phase III. Sponsor Allergan. Allergan. Status Ongoing. Ongoing. Source of Trial registry 24, manufacturer. Trial registry, manufacturer. information Location EU, USA, Canada and other countries. EU (inc UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants and schedule n=510 (planned); adults; DMO; VA 20/50 or worse in study eye; VA in other eye 20/200 or better. Randomised to DEX PS DDS 350µg IVT injection; DEX PS DDS 700µg IVT injection; or sham IVT needle-less DEX PS DDS. All administered on day 1, then if required at a minimum 6-month treatment interval for up to a total of 7 treatments. n=510 (planned); adults; DMO; VA 20/50 or worse; VA in other eye 20/200 or better. Randomised to DEX PS DDS 350µg IVT injection; DEX PS DDS 700µg IVT injection; or sham IVT needle-less DEX PS DDS. All administered on day 1, then if required at a minimum 6-month treatment interval for up to a total of 7 treatments. Follow-up Active treatment period 39 months. Active treatment period 39 months. a Expert communication. 4

5 Primary outcome Secondary outcomes Expected reporting date Best Corrected Visual Acuity (BCVA) BCVA improvement 15 letters. improvement 15 letters. Change in BCVA; contrast sensitivity; Change in BCVA; contrast sensitivity; vessel leakage as measured by vessel leakage by FA; retinal thickness Fluorescein Angiography (FA); retinal by OCT. thickness as measured by Optical Coherence Tomography (OCT). Jun Jun Trial NCT , DC ; DEX PS DDS 350µg, 700μg or observation; phase II. NCT , ; DEX PS DDS 700μg; phase II. NCT , ; DEX PS DDS 700μg or sham both with laser treatment; phase II. Sponsor Allergan. Allergan. Allergan. Status Published. Published. Complete but unpublished. Source of Publication 26,27,28, trial Publication, trial Trial registry, information registry 29, manufacturer. registry 31, manufacturer. manufacturer. Location USA. USA and Australia. USA and Canada. Design Randomised, observationcontrolled. Non-randomised, single arm. Randomised, placebocontrolled. Participants and schedule Follow-up Primary outcome Secondary outcomes Key results n=315; 12 years old; persistent MO associated with diabetic retinopathy, uveitis, retinal vein occlusion, or Irvine-Gass syndrome; persisting 90 days after laser treatment or medical management. Randomised to DEX PS DDS 350µg, or 700µg, both administered surgically; or observation. Active treatment period 90 days; then 90 days follow up. BCVA improvement 10 letters. BCVA improvement 15 letters; vessel leakage by FA 3-grade improvement b ; central retinal thickness (CRT) by OCT; safety. DMO patients, DEX PS DDS 350µg (n=57), DEX PS DDS 700µg (n=57) vs observation (n=57) respectively (p vs placebo): BCVA improvement 10 letters at day 90, 21.1%, n=56; adults; DMO; vitrectomy; CRT 275µm; VA between 20/320 and 20/40 in study eye; VA in other eye 20/200 or better. Subject received single 700µg DEX PS DDS IVT injection. Active treatment period 26 weeks. Change in mean CRT by OCT. BCVA improvement 10 letters; vessel leakage by c FA; NEI-VFQ-25 scale. Mean change in CRT at week 8, -156µm (95% CI, -190 to -122µm); mean change in CRT at week 26, -39µm (95% CI, -65 to -13µm); mean change in BCVA at week 8, +6.0 letters (95% CI, +3.9 to n=253; adults; DMO; VA 20/50 or worse in study eye; VA in other eye 20/200 or better. Randomised to DEX PS DDS 700µg or sham, all administered by IVT injection, every 6 months for up to 2 doses in combination with laser treatment. Active treatment period 12 months; then up to 13 weeks follow up. BCVA improvement 10 letters. VA change; BCVA improvement 15 letters; macular thickness by OCT; vessel leakage by FA; quality of life; time to retreatment. Not available. b Standardised 9-grade scale. c National Eye Institute Visual Function Questionnaire-25. 5

6 Adverse effects (AEs) 33.3% vs 12.3% (p=0.007); BCVA improvement 10 letters at day 180, 19%, 30% vs 23% (p 0.40); mean change in CRT at day 90, -42.6µm (p<0.07), µm (p<0.001) vs +30.2µm; 2 levels of improvement in vessel leakage (FA), 22.2% (p=0.01), 36.4% (p<0.001) vs 5.4% ; 3 levels of improvement in vessel leakage (FA), 13.0% (p=0.03), 27.3% (p<0.001) vs not reported. DEX PS DDS 350µg (n=55), 700µg (n=53) vs observation (n=57), respectively (p vs observation): anterior chamber inflammatory cells present, 29.1%, 26.4% vs 1.8% (p<0.001); anterior chamber flare, 27.3%, 20.8% vs 8.8% (p=0.04); vitreous haemorrhage, 20.0%, 22.6% vs 5.3% (p=0.02); eye pain, 18.2%, 9.4% vs 3.5% (p=0.04); reduced VA, 16.4%, 17.0% vs 10.5% (p=0.57) vitreous disorder, 20.0%, 15.1% vs 3.5% (p=0.03); increased IOP, 14.5%, 9.4% vs 0% (p=0.006); conjunctival haemorrhage, 14.5%, 7.5% vs 0% (p=0.005); maculopathy, 12.7%, 7.5% vs 1.8% (p=0.08); eye irritation,12.7%, 15.1% vs 3.5% (p=0.10); vitreous floaters, 7.3%, 17.0% vs 0% (p=0.001); abnormal sensation in eye, 7.3%, 15.1% vs 3.5% (p=0.10); MO, 16.4%, 5.7% vs 8.8% (p=0.17); eye pruritus, 10.9%, 7.5% vs 1.8% (p=0.12); retinal haemorrhage, 10.9%, 11.3% vs 21.1% (p=0.23); +8.1 letters); mean change in BCVA at week 26, +3.0 letters (+0.1 to +6.0 letters); proportion of patients with 10 letter improvement in BCVA at weeks 8 and 13, 30%; proportion of patients with 10 letter improvement in BCVA at week 26, 21%. AEs related or unrelated to treatment: conjunctival haemorrhage, 52.7%; conjunctival hyperaemia, 20.0%; eye pain, 16.4%; increased IOP, 16.4%; conjunctival oedema, 12.7%; vitreous haemorrhage, 10.9%; epiretinal membrane, 3.6%; macular thickening, 3.6%; anterior chamber inflammatory cells present, 5.5%; foreign body sensation, 5.5%; iritis, 5.5%; myodesopsia, 5.5%. Not available. 6

7 Trial other diabetic retinopathy, 5.5%, 11.3% vs 14.0% (p=0.31). NCT , IIT-406; DEX PS DDS 700μg or intravitreal bevacizumab 1.25mg; phase II. NCT , NHMRC project , ; DEX PS DDS 700μg or intravitreal bevacizumab 1.25mg; phase II. Sponsor Retina Macula Institute. University of Sydney. Status Ongoing. Ongoing. Source of Trial registry 33, manufacturer. Trial registry, manufacturer. information Location USA. Australia. Design Randomised, active-controlled. Randomised, active-controlled. Participants and schedule Follow-up Primary outcomes Secondary outcomes Expected reporting date Trial n=20 (planned); adults; DMO; prior treatment with 3 prior IVT anti-vegf injections; ETDRS VA 3-78 letters. Randomised to DEX PS DDS 700µg at months 0 and 4, or intravitreal bevacizumab 1.25mg given at initial visit then once monthly for 5 treatments in total, all administered by IVT injection. Active treatment period 6 months. Any ongoing drug-related SAEs followed until resolution or determined to be irreversible, chronic, or stable by the investigator. VA; central foveal thickness by OCT. Macular leakage by FA; mean macular sensitivity on microperimetry; mean central amplitude on multi-focal electroretinography. Jun Jul NCT , ; DEX PS DDS 700μg or ranibizumab 0.5mg; phase II. n=80 (planned); adults; DMO; untreatable with laser therapy; BCVA letters (6/12 6/120); retinal thickness >250µm (OCT); increased IOP <22mmHg. Randomised to DEX PS DDS 700µg at day 1 with at least a 16-week interval between subsequent treatments; or intravitreal bevacizumab 1.25mg every 4 weeks for 3 treatments, and then given as needed once every 4 weeks. Active treatment period 102 weeks; final safety visit with no treatment at week 104. BCVA improvement 10 letters. Change in VA; change in OCT; laser requirement; patient satisfaction; safety. OZLASE, EUCTR GB, ; DEX PS DDS 700μg with deferred macular laser therapy or placebo with macular laser therapy; phase III. Sponsor Allergan. Moorfields Eye Hospital R&D Department. Status Ongoing. Ongoing. Source of Trial registry 35, manufacturer. Trial registry, manufacturer. information Location EU (inc UK), USA and Israel. UK. Design Randomised, active-controlled. Randomised, active-controlled. 7

8 Participants and schedule Follow-up Primary outcome Secondary outcomes Expected reporting date n=300 (planned); adults; DMO; VA n=80 (planned); adults; DMO; Snellen between 20/200 to 20/40. VA 6/24 6/9 d. Randomised to DEX PS DDS 700μg on Randomised to DEX PS DDS 700µg on day 1 and months 5 and 10, or day 1 and week 16, with DEX PS DDS ranibizumab 0.5mg monthly. All and laser combination treatment, if administered by IVT injection. required, on week 32 or 48; or placebo with macular laser therapy on day 1 and week 16 with retreatment, if required, on week 32 or 48. Active treatment period 12 months. No Active treatment period 48 weeks; then 8 follow up period. weeks follow up. Change in BCVA. Mean best corrected ETDRS VA letter score at 56 weeks. Foveal thickness by OCT; total area of BCVA gain 10 letters; BCVA gain 15 macular leakage by FA. letters; BCVA loss <15 letters; average of the mean change in VA at each intervening timepoint to week 56; mean difference in BCVA letter score at weeks 24 and 40; proportion of subjects who have lost 30 letters; mean difference in central subfield thickness at week 56; change in domain scores of the VFQ-25 e and EQ-5D f ; number of treatments. Jan Dec Estimated cost and cost impact The cost of Ozurdex for this indication is not yet known, however the cost for the treatment of MO secondary to retinal vein occlusion is 870 for 700µgs in a disposable applicator. In 2010, the cost of laser therapy for the first year of treatment based on mean utilisation was 1,241-1, The cost of other treatment options are: Drug Dose 38 Cost 15 Bevacizumab 1.25mg IVT injection. Estimated annual cost 4,278. (Avastin) Ranibizumab (Lucentis) 500µg IVT injection. Estimated annual cost 4,668-9,336. Claimed or potential impact speculative Patients Reduced mortality or increased length of survival Other: Reduction in associated morbidity or improved quality of life for patients and/or carers Quicker, earlier or more accurate diagnosis or identification of disease None identified Services Increased use Service organisation Staff requirements Decreased use Other: None identified d BCVA in the study eye between 54 and 78 letters at 1m. e National Eye Institute Visual function questionnaire. f EuroQol Group measure of health outcome. 8

9 Costs Increased unit cost compared to alternative New costs: Increased costs: more patients coming for treatment Savings: reduced unit cost and fewer injections compared to anti- VEGF treatments. Increased costs: capital investment needed Other: Other issues Clinical uncertainty or other research question identified: None identified References 1 Bhagat N, Grigorian RA, Tutela A et al. Diabetic macular edema: pathogenesis and treatment. Survey of Ophthalmology 2009;54: The Royal College of Ophthalmologists. Guidelines for diabetic retinopathy. London: Royal College of Ophthalmologists; Cheung CM, Vania M, Ang M et al. Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy. Molecular Vision 2012;18: Zur D and Loewenstein A. Combination therapy for diabetic macular edema. Journal of Ophthalmology 2012; doi: /2012/ The electronic Medicines Compendium (emc). Summary of product characteristics, Ozurdex. Allergan Ltd, January London NJ, Chiang A and Haller JA. The dexamethasone drug delivery system: indications and evidence. Advances in Therapy. 2011;28(5): National Institute for Health and Clinical Excellence. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular oedema. Technology appraisal in development ID419. London: NICE; Expected November National Institute for Health and Clinical Excellence. Dexamethasone intravitreal implant for the treatment of macular oedema secondary to retinal vein occlusion. Technology appraisal TA229. London: NICE; July National Institute for Health and Clinical Excellence. Ranibizumab for the treatment of diabetic macular oedema. Technology appraisal TA237. London: NICE; November National Institute for Health and Clinical Excellence. Quality standards. Diabetes in adults quality standard. Accessed 3 May National Institute for Health and Clinical Excellence. Type 2 diabetes: the management of type 2 diabetes. Clinical guideline CG87 (partial update of CG66). London: NICE; May National Institute for Health and Clinical Excellence. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people, and adults (updated). Clinical guideline CG15. London: NICE; July Scottish Medicines Consortium. SMC advice. Ranibizumab. Treatment of visual impairment due to diabetic macular oedema in adults. July _FINAL_JUNE_2011_amended_050711_for_website.pdf 14 SIGN. Management of diabetes. A national clinical guideline. SIGN 116. March North East Treatment Advisory Group (NETAG) appraisal and recommendation: Anti-vascular endothelial growth factor therapies (bevacizumab and ranibizumab) for diabetic macular oedema. October The Royal College of Ophthalmologists. Guidelines for intravitreal injections procedure. London: Royal College of Ophthalmologists; Minassian DC, Owens DR and Reidy A. Prevalence of diabetic macular oedema and related health and social care resource use in England. The British Journal of Ophthalmology 2012;96(3): National Institute for Health and Clinical Excellence. Final scope for the appraisal of fluocinolone acetonide intravitreal implant for the treatment of chronic diabetic macular oedema. October Fong DS, Cavallerano JD, Aiello L et al. Retinopathy in diabetes. American Diabetes Association Position Statement. Diabetes Care 2004;27 (1):s84-s Gulliford MC, Dodhia H, Chamley M et al. Socio-economic and ethnic inequalities in diabetes retinal screening. Diabetic Medicine 2010;27(3): Royle P, Cummins E, Henderson R et al. Ranibizumab for the treatment of diabetic macular oedema: a single technology appraisal. Aberdeen HTA Group January Klein BE. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiology 2007;14: Map of Medicine. Diabetic retinopathy. Other treatment options. July

10 24 ClinicalTrials.gov. A study of the safety and efficacy of a new treatment for diabetic macular edema. Accessed 27 April ClinicalTrials.gov. A study of the safety and efficacy of a new treatment for diabetic macular edema. Accessed 27 April Kuppermann BD, Blumenkranz MS, Haller JA et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Archives of Ophthalmology. 2007;125(3): Kuppermann BD, Chou C, Weinberg DV et al. Intravitreous dexamethasone effects on different patterns of diabetic macular edema. Archives of Ophthalmology 2010;128: Haller JA, Kuppermann BD, Blumenkranz MS et al. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Archives of Ophthalmology. 2010;128(3): ClinicalTrials.gov. Research study in patients with persistent macular edema Accessed 30 April Boyer DS, Faber D, Gupta S et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31(5): ClinicalTrials.gov. Safety and efficacy of a new treatment in vitrectomized subjects with diabetic macular edema. Accessed 27 April ClinicalTrials.gov. Safety and efficacy of a new treatment in combination with laser for diabetic macular edema. Accessed 30 April ClinicalTrials.gov. Ozurdex for treatment of recalcitrant diabetic macular edema. Accessed 30 April ClinicalTrials.gov. Intravitreal bevacizumab (Avastin) versus intravitreal dexamethasone (Ozurdex ) for persistent diabetic macular oedema. Accessed 30 April ClinicalTrials.gov. Safety and efficacy study of dexamethasone versus ranibizumab in patients with diabetic macular edema Accessed 30 April WHO International Clinical Trials Registry. A prospective randomised controlled trial of intravitreal ozurdex and macular laser therapy versus macular laser therapy only in diabetic macular oedema (OZLASE study). Accessed 27 April EU Clinical Trials Register. A prospective randomised controlled trial of intravitreal ozurdex and macular laser therapy versus macular laser therapy only in diabetic macular oedema (OZLASE study). Accessed 27 April British Medical Association and Royal Pharmaceutical Company of Great Britain. British National Formulary. BNF 63. London: BMJ Group and RPS Publishing, March The National Institute for Health Research Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health The NIHR Horizon Scanning Centre, Department of Public Health, Epidemiology and Biostatistics University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SQ, England Tel: +44 (0) Fax +44 (0)