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Dexamethasone intravitreal implant (Posurdex) for macular oedema

Source agency:

NHSC

Date of Submission:

05/11/2009

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Dexamethasone intravitreal implant

Technology - description:

Dexamethasone intravitreal implant (Posurdex) is a biodegradable drug delivery system (DDS) that is implanted by intravitreal (IVT) injection where it delivers dexamethasone to the posterior segment of the eye for up to six months, biodegrading to release carbon dioxide and water. Dexamethasone is a corticosteroid that acts as a glucocorticoid receptor agonist to suppress inflammation.



Posurdex is currently in phase III clinical trials for diabetic macular oedema and uveitis and phase II trials for age related wet macular degeneration.

Company or developer:

Allergan.

Reason for database entry:

This will be one of the first pharmacological agents licensed for the treatment of macular oedema secondary to BRVO and CRVO.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Investigational - phase III

Licensing, reimbursement and other approval:

 

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

• Macular oedema secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO).

Disease description and associated mortality and morbidity:

Retinal vein occlusion (RVO) is a common vascular disorder of the retina and can lead to severe visual loss. It is classified into central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) based on the site of obstruction. CRVO results from thrombosis of the central retinal vein at the level of the lamina cribrosa, whereas BRVO is caused by venous thrombosis at an arteriovenous crossing, where an artery and vein share a common adventitial sheath. Thrombosis of the retinal veins causes an increase in retinal capillary pressure resulting in increased capillary permeability and the exudation of blood and plasma into the retina. This leads to the development of macular oedema and varying levels of ischaemia through non-perfusion of capillaries. These changes trigger up-regulation of vascular endothelial growth factor (VEGF), which increases vascular permeability and new vessel proliferation.

Number of Patients:

RVO is the second most common retinal vascular disorder after diabetic retinopathy, with a prevalence varying between 0.7% and 1.6% (1). In a population based study, the incidences of BRVO and CRVO were 1.8% and 0.5% respectively (2). Incidence typically increases with age, with over 50% of people with CRVO being aged 65 and over (3).

Non-ischaemic CRVO presents with mild to moderate visual loss (6/18 or better in 80%), but may progress to the ischaemic type associated with poor vision (3/60 or worse in 87%) and a greater than 60% risk of iris neovascularisation (INV) and neovascular glaucoma (NVG) . BRVO presents with a variable degree of visual loss with neovascularisation of the retina occurring in 20% of cases (4). Approximately 50-60% of untreated eyes with BRVO retain a visual acuity of 6/12 or better after one year whilst 25% will have vision of less than 6/20 (4,5). Complications associated with BRVO are similar to those of CRVO, but are limited in scope because only part of the retina is drained by the involved branch.

The impact of visual disturbance and vision loss associated with CRVO and BRVO can have a profound impact on (vision-related) quality of life, especially if the other eye is already affected. Patients may struggle with daily tasks, lose confidence and become increasingly dependent on family/carers. Retinal vein occlusions are also associated with an increase in vascular causes of death (both cerebral and cardiac) in large prospective follow up studies (5).

Technology - specialities(s):

Ophthalmology

Technology - setting(s):

None

Setting - further information:

 

Impact

Alternative and/or complementary technology:

 

Current Technology:

Assessment and management of BRVO:

• Fluorescein angiogram to determine factors such as pattern of fluid leakage and presence of ischaemia.

• Grid laser photocoagulation for the treatment of macular oedema in BRVO if visual acuity is less than 6/12 for three months.

• Scatter laser photocoagulation for the treatment of neovascularisation in BRVO.

• Intravitreal triamcinolone (corticosteroid) as a primary or adjunctive treatment for macular oedema (not licensed).

• Arteriovenous sheathotomy (AVS).

Management options for CRVO:

• Panretinal photocoagulation for ischaemic CRVO.

• Intravitreal triamcinolone (corticosteroid) for the treatment of macular oedema (not licensed).

Health Impact:

 

Diffusion:

 

Cost, infrastructure and economic consequences:

 

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Trial: NCT00035906; DC-103-06-03; Posurdex vs observation; phase II.

Sponsor: Oculex Pharmaceuticals, Allergan.

Status: Published (6).

Location: USA.

Design: Randomised, dose range, stratified by underlying cause.

Participants and schedule: n=315; over 12 years; due to diabetic retinopathy; CRVO (n=42); BRVO (n=60); uveitis or Irvine-Gass syndrome; BCVA 20/40 (67-73 letters) to 20/200 (34-38 letters); stratified by underlying cause; no steroids within 30 days.

Randomised to dexamethasone DDS 350µg, 700µg (by incisional placement with sutures) or observation. No supplementary treatments allowed in trial eye within 90 days unless medically necessary.

Follow-up: 180 days.

Primary outcome: >10 letters improvement in best-corrected visual acuity (BCVA) at 90 days.

Secondary outcomes: >15 letter improvement in BCVA, improvement in vessel leakage, central retinal thickness (selected trial sites only), safety.

Key results: Intention to treat analysis. For dexamethasone DDS 350µg, 700µg and observation respectively:

Day 90 >10 letter improvement in 24%, 35% and 13% (p=0.04 and p<0.001 vs. observation).

Day 90 >15 letter improvement in 10%, 18% and 6% (p=0.28 and p=0.006 vs. observation).

Use of additional non-study treatments in 12%, 9% and 24% (p=0.003 and p=0.03 vs. observation).

Day 180 >15 letter improvement with dexamethasone DDS 700 µg 18% vs. 8% for observation (p=0.02).

Efficacy results similar, but not all significant between underlying causes.

Significant improvement in vessel leakage and retinal thickness with dexamethasone DDS.

Adverse effects : Adverse effects significantly associated with dexamethasone DDS included anterior chamber flare after day 8 (5% vs. 0% with observation) and increased intraocular pressure between days 91 and 180 (6% vs. 0%). Vitreous haemorrhage (most within week 1) reported in 43/210 receiving dexamethasone DDS.



Trial: NCT00168324 (7); 206207-008: Posurdex vs sham injection; phase III.

Sponsor: Oculex Pharmaceuticals, Allergan.

Status: Completed, unpublished (9).

Location: North America, South America, Europe, Asia, Israel, South Africa.

Design: Randomised, double blind, dose comparison.

Participants and schedule: n=567; adults; retinal vein occlusion due to CRVO or BRVO.

Randomised to 700µg Posurdex at months 0 and 6; 350µg Posurdex at month 0; or sham injection at month 0.

All patients offered 700µg Posurdex in extension phase.

Follow-up: 6 months masked then 6 months open label.

Primary outcome: Visual acuity, time to ≥15 letters improvement in BCVA.

Secondary outcomes: Visual acuity, contrast sensitivity, vessel leakage, quality of life questionnaire.

Key results: Pooled results: Posurdex led to statistically significant improvement in vision, based on a 3-line or better improvement in BCVA compared to sham treatment. This improvement occurred in the first two months for 20-30% of the patients treated.

Expected reporting date : Second half of 2009.

Adverse effects: Less than 7% of those receiving Posurdex experienced elevation of intraocular pressure (IOP) ≥35mm Hg in first 6 months. At 6 months <1% of patients had IOP above 25mm Hg.



Trial: NCT00168298 (8); 206207-009: Posurdex vs sham injection; phase III.

Sponsor: Oculex Pharmaceuticals, Allergan.

Status: Completed, unpublished (9).

Location: North America, South America, Europe, Asia, Israel, South Africa.

Design: Randomised, double blind, dose comparison.

Participants and schedule: n=629; adults; retinal vein occlusion due to CRVO or BRVO.

Randomised to 700µg Posurdex at months 0 and 6; 350µg Posurdex at month 0 or sham injection.

All patients offered 700µg Posurdex in extension phase.

Follow-up: 6 months masked then 6 months open label.

Primary outcome: Visual acuity, time ≥15 letters improvement in BCVA.

Secondary outcomes: Visual acuity, contrast sensitivity, vessel leakage, quality of life questionnaire.

Key results: Pooled results: Posurdex led to statistically significant improvement in vision, based on a 3-line or better improvement in BCVA compared to sham treatment. This improvement occurred in the first two months for 20-30% of the patients treated.

Expected reporting date : Second half of 2009.

Adverse effects: Less than 7% of those receiving Posurdex experienced elevation of intraocular pressure (IOP) ≥35mm Hg in first 6 months. At 6 months <1% of patients had IOP above 25mm Hg.

Economic evaluation:

 

Ongoing research:

 

Ongoing or planned HTA:

 

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

1: Rehak J and Rehak M. Branch retinal vein occlusions: pathogensis, visual prognosis, and treatment modalities. Current Eye Research 2008; 33: 111-131.

2: Klein R, Moss SE, Meuer SM et al. The 15-year cumulative incidence of retinal vein occlusion: the beaver dam eye study. Archives of Ophthalmology 2008: 126; 513–518.

3: Fegan CD. Central retinal vein occlusion and thrombophilia. Eye 2002; 16: 98-106.

4: The Royal College of Opthalmologists. Retinal vein occlusions. 2006. http://www.rcophth.ac.uk/docs/members /focus-collegenews/FocusAutumn06.pdf

5: The Royal College of Ophthalmologists. Retinal vein occlusion (RVO) interim guidelines. February 2009.

6: Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomised controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular oedema. Archives of Ophthalmology. 2007;125:309-317.

7: ClinicalTrials.gov. A study of the safety and efficacy of a new treatment for macular oedema resulting from retinal vein occlusion. http://www.clinicaltrials.gov/ct2/show/NCT00168324?term=Posurdex&rank=2
Accessed 28th May 2009.

8: ClinicalTrials.gov. A study of the safety and efficacy of a new treatment for macular oedema resulting from retinal vein occlusion. http://www.clinicaltrials.gov/ct2/show/NCT00168298?term=Posurdex&rank=5
Accessed 28th May 2009.

9: Allergan press release. Allergan Reports third quarter 2008 operating results.
http://agn.client,shareholder.com/earningsreleasedetail.cfm?ReleaseID=343731 Accessed on 4th June 2009.

Notes: