Aganirsen for pathological corneal neovascularisation

Transcription

1 Aganirsen for pathological corneal neovascularisation August 2011 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 National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

2 Aganirsen for pathological corneal neovascularisation Target group Pathological corneal neovascularisation (CoNV). Technology description Aganirsen is an antisense oligonucleotide against the insulin receptor substrate-1 (IRS-1). Antisense oligonucleotides are short, synthetic oligonucleotides which are complementary in sequence and function by specific hybridisation to their cognate gene product (mrna), inducing inhibition of gene expression. IRS-1 is known to be overexpressed in pro-angiogenic conditions, and by reducing the over-expression of IRS-1 associated with pathological neovascularisation, aganirsen regulates both the expression of angiogenic growth factors and inflammatory cytokines 1. Aganirsen is administered via twice daily eye drops at a total dose of 86µg daily for 2-6 months depending on the spread and degree of pathological neovasularisation. Aganirsen is in phase II trials for psoriasis and rosacea. Innovation and/or advantages If licensed, aganirsen may offer a new pharmacological treatment option with the potential to improve outcomes in patients who currently have limited therapeutic options, and it may also reduce the risk of rejection in patients who subsequently undergo corneal grafts. Developer Gene Signal International SA. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to The National Service Framework for Long-term Conditions (200). Relevant guidance NICE interventional procedure guidance. Corneal endothelial transplantation NICE interventional procedure guidance. Tissue-cultured limbal stem cell allograft transplantation for regrowth of corneal epithelium Clinical need and burden of disease The cornea is normally avascular which is important in maintaining its clarity. CoNV is a sight-threatening condition usually associated with disorders of the ocular surface 4, and is one of the most common manifestations associated with a range of eye diseases, including inflammatory and infectious disorders, bacterial pathogens and extended use of contact lenses. CoNV results from the growth of new vessels into the cornea which change the ocular surface microenvironment leading to corneal opacity 6. Neovascularisation leads to tissue scarring, lipid deposition, stromal haemorrhage and oedema of the cornea, severely altering visual acuity (VA). In addition, vascularisation also introduces circulating immune cells, reducing the immune privilege of the cornea and the graft survival of a subsequent penetrating keratoplasty (PKP). 2

3 Neovascularisation occurs in many eye diseases, and its impact is thought to be significant. However, information on the prevalence and incidence of CoNV in the UK is sparse. In the United States, CoNV has been reported in 4.14% of patients presenting for general ophthalmic care 7. In , there were 69 hospital admissions for CoNV in England, accounting for 12 bed days 8. Graft rejection is a leading cause of failure of PKP whilst the success rate for this type of graft is close to 90%, where considerable CoNV exists, rejection frequency is reduced to between 3.% and 6% 9. In , there were 3,061 corneal grafts in the UK, equating to 4.96 per 100,000 population 10. Existing comparators and treatments There are currently no drugs licensed for the treatment of pathological CoNV alone, or in association with a planned graft. Unlicensed options include photodynamic therapy, VEGF inhibitors and restoration of the ocular surface 11. Conventional therapies such as corticosteroids and immunosuppressants are only partly effective and are associated with severe side effects. Efficacy and safety Trial , GS101-P3-CG, The I-GRAFT Study; adults; aganirsen vs placebo; phase III , GS101-P2-CG, CN ; adults; aganirsen vs placebo; phase II. Sponsor Les Laboratoires CTRS. Les Laboratoires CTRS. Status Ongoing. Published. Source of Trial registry 12, manufacturer Abstract, publication, trial registry 14. information Location EU. EU. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants and schedule n=64 (planned); adults; keratitis or keratouveitis of bacterial, viral or traumatic origin with stromal neovascularisation. Randomised to aganirsen, 0µl, or placebo, as 2 eye drops, 1 in the morning and 1 in the evening. Follow-up Active treatment period 3 months; 6 months follow-up. Primary VA. outcome Secondary Corneal angiogenesis; quality of life; outcomes need for transplantation; risk of graft n=40; adults, keratitis or keratouveitis of infectious, inflammatory or traumatic origin with stromal neovascularisation. Randomised to aganirsen, 43, 86 or 172µg, or placebo, as 2 eye drops, 1 in the morning and 1 in the evening. Active treatment period 6 months. Corneal (epithelial or stromal) neovascularisation. VA. rejection. Key results - At 3 months, for aganirsen 43, 86, 172µg, and placebo respectively (p-value vs placebo): change in neovascularised area (% of total corneal area), mean±sd, 0.07±2.94, -2.04±1.7, 1.60±7.63, 0.89±2.1; progression/regression of neovascularisation (%), 66.7/33.3 (p=0.44), 14.3/8.7 (p=0.004), 62./37. (p=0.208), 100.0/0.0. Expected reporting date Not reported. - 3

4 Adverse effects (AEs) - 7 reported AEs, including mild (68%), moderate (2%), severe (7%). Estimated cost and cost impact The cost of aganirsen is not yet known. 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 Costs Decreased use: potential for reduced transplant rejection Increased unit cost compared to alternative New costs: additional treatment Other: new outpatient treatment option Increased costs: more patients coming for treatment Savings: potential for reduced transplant rejection None identified Increased costs: capital investment needed Other: Other issues Clinical uncertainty or other research question identified: None identified References 1 Al-Mahmood S, Colin S, Farhat N et al. Potent in vivo antiangiogenic effects of GS-101 ( - TATCCGGAGGGCTCGCCATGCTGCT-3 ), an antisense oligonucleotide preventing the expresson of insulin receptor substrate-1. Journal of Pharmacology and Experimental Therapeutics 2009;329(2): National Institute for Health and Clinical Excellence. Corneal endothelial transplantation: guidance. Interventional procedure guidance IPG304. London: NICE; June National Institute for Health and Clinical Excellence. Tissue-cultured limbal stem cell allograft transplantation for regrowth of corneal epithelilum. Interventional procedure guidance IPG216. London: NICE; April Chang JH, Gabison EE, Kato T et al. Corneal neovascularisation. Current Opinion in Ophthalmology 2001;12(4): Maddula S, Davis DK, Maddula BA et al. Horizons in therapy for corneal angiogenesis. Ophthalmology 2011;118: Gunda V, Wang S, Sheibani N et al. Inhibitory effect of tumstatin on corneal neovascularisation both in-vitro and in-vivo. Clinical and Experimental Ophthalmology 2011;2(2): Lee P, Want CC, Adamis A. Ocular neovascularisation: an epidemiologic review. Survey of Ophthalmology 1998:43(3): NHS. Hospital Episode Statistics. NHS England HES data Sellami D, Abid G, Bouaouaja S et al. Epidemiology and risk factors for corneal graft rejection. Transplantation Proceedings 2007;39: NHS Blood and Transplant. Activity report : transplant activity in the UK Accessed 26 May Cursiefen C, Bock F, Horn FK et al. GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularisation: interim results of a randomized phase II trial. Ophthalmology 2009;116:

5 12 EudraCT. A multicentre double-blind randomized study to investigate the efficacy and tolerability of GS-101 eye drops, an antisense oligonucleotide, versus placebo on inhibition of corneal neovascularisation, a major risk factor of corneal graft rejection: the I-GRAFT study. Accessed 24 May Cursiefen C, Bock F, Kruse FE et al. Antisense oligonucleotide eye drops against IRS-1 inhibit corneal neovascularisation: interim results of a randomized phase II clinical trial. Investigative Ophthalmology and Visual Science 2009;0:E-Abstract EudraCT. A multicenter double-blind randomized study to investigate the efficacy and tolerability of three doses of GS-101 eye drops, an antisense oligonucleotide, versus placebo on inhibition of corneal neovascularisation, a major risk factor of corneal graft rejection. Accessed 24 May The National Institute for Health Research National 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 National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B1 2SP, England Tel: +44 (0) Fax +44 (0)