Horizon Scanning Centre July 2013

Gevokizumab for chronic non- infectious uveitis

SUMMARY NIHR HSC ID: 8064

Gevokizumab is an anti-inflammatory humanised IgG2 that binds to -1ß (IL-1ß). It is intended for treatment of chronic, non-infectious uveitis, including that associated with Behҫet’s disease. Binding to IL-1ß blocks the activation of the IL-1 receptor preventing cellular signalling events that produce inflammation. Gevokizumab is intended for monthly subcutaneous (SC) dosing.

Uveitis is inflammation of the uveal tract of the eye, which consists of the iris, This briefing is the ciliary body and the choroid. Inflammation of nearby tissues, such as the based on retina, the optic nerve, and the vitreous humour may also occur. Uveitis may information be classified by the anatomical location of the pathology: anterior, available at the time intermediate (vitritis), posterior (retina and choroid) or panuveitis. Chronic of research and a uveitis may be defined as active uveitis that persists longer than three limited literature months. Symptoms of uveitis include: pain, redness, photophobia, search. It is not headaches, visual floaters and decreased visual acuity. Non-infectious intended to be a uveitis may be due to an underlying inflammatory condition, an autoimmune definitive statement disorder or occur as a result of trauma to the eye. In many cases the cause on the safety, remains uncertain. Systemic diseases such as Behҫet’s disease and efficacy or sarcoidosis can be associated with either acute or chronic uveitis. Ocular effectiveness of the involvement is common in Behçet’s disease, and may cause severe uveitis. health technology covered and should The overall incidence of uveitis is estimated to be between 17 and 52.4 per not be used for 100,000 population equating to between 9,500 and 29,200 new cases per commercial year in the UK. Posterior segment uveitis is less common than anterior purposes or uveitis and tends to be more severe; posterior segment uveitis accounts for commissioning around 1 in 5 cases. It is estimated that non-infectious posterior segment without additional uveitis affects around 3 to 10 people per 100,000 in the European Union. information. This would equate to between 1,500 and 5,000 cases per year in England. The prevalence of Behҫet’s disease in the UK is estimated at 0.64 per 100,000 population, which equates to approximately 400. Approximately 50- 70% of patients with Behҫet’s disease have uveitis and current estimates indicate that severe visual impairment occurs in 25% of involved eyes.

Gevokizumab is currently in three phase III clinical trials assessing its efficacy compared with placebo.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Uveitis: chronic; non-infectious. • Uveitis: patients with Behҫet’s disease.

TECHNOLOGY

DESCRIPTION

Gevokizumab (XOMA-052) is an anti-inflammatory humanized IgG2 monoclonal antibody \that binds to interleukin-1ß (IL-1ß). It is intended for treatment of chronic, non-infectious uveitis, including that associated with Behҫet’s disease. Binding to IL-1ß blocks the activation of the IL-1 receptor preventing cellular signalling events that produce inflammation. Gevokizumab is intended for monthly subcutaneous (SC) dosing.

Gevokizumab is also in phase II development for rheumatoid arthritis and scleritis.

INNOVATION and/or ADVANTAGES

If licensed, gevokizumab will offer an alternative treatment option for this patient group.

DEVELOPER

SERVIER.

AVAILABILITY, LAUNCH OR MARKETING

Gevokizumab is a designated orphan drug in the EU and the USA for the treatment of chronic non-infectious uveitis.

Gevokizumab is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Uveitis is inflammation of the uveal tract of the eye, which consists of the iris, the ciliary body and the choroid. Inflammation of nearby tissues, such as the retina, the optic nerve, and the vitreous humour may also occur1. Uveitis may be classified by the anatomical location of the pathology: anterior, intermediate (vitritis), posterior (retina and choroid) or panuveitis. The course of uveitis may be acute, recurrent or chronic2,3. Chronic uveitis can be differentiated from acute recurrent uveitis by its rate of progression and may be defined as active uveitis that persists longer than three months4. Symptoms of uveitis can include: pain, redness, photophobia, headaches, visual floaters and decreased visual acuity3. Non-infectious uveitis may be due to an underlying inflammatory condition, an autoimmune disorder or occur as a result of trauma to the eye. In many cases the cause remains uncertain5,6. Systemic diseases such as Behҫet’s disease and sarcoidosis can be associated with either acute or chronic uveitis4. Ocular involvement is common in Behçet’s disease, and may cause severe uveitis7.

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NHS or GOVERNMENT PRIORITY AREA

None identified.

CLINICAL NEED and BURDEN OF DISEASE

Ocular inflammatory diseases are an important cause of blindness (BCVAa < 20/400) or low vision (BCVA between 20/70 and 20/200) worldwide8,9. Non-infectious uveitis is frequently associated with a substantial burden of co-morbidity and with systemic disease in around one-third of cases10. Associated co-morbidities generally have a strong autoimmune component e.g. rheumatoid arthritis and psoriatic dermatologies11. It is often the extra-ocular symptoms of underlying inflammatory or autoimmune conditions which are the primary focus of treatment for these, with uveitis considered as a secondary manifestation11. Chronic uveitis is associated with a high incidence of vision threatening complications such as cataract, macular oedema, and glaucoma4. Consequently uveitis is a leading cause of visual impairment in the UK12. In countries of the developed world, uveitis is the cause of about 1 in 10 cases of visual impairment3 with approximately 35% of patients reporting blindness or low vision in one eye3,10,13,. Uveitis most commonly affects people aged 20 to 59, but may also occur in children3. Men and women are equally affected1. The existence of self-resolving forms of uveitis makes it difficult to ascertain its true incidence. However, the overall incidence is estimated to be between 17 and 52.4 per 100,000 population equating to between 9,500 and 29,200 new cases per year in the UK3,11,14,15. Posterior segment uveitis is less common than anterior uveitis and tends to be more severe; posterior segment uveitis accounts for around 1 in 5 cases10. It is estimated that non-infectious posterior segment uveitis affects around 3 to 10 people per 100,000 in the EU. This would equate to between 1,500 and 5,000 cases per year in England16.

The prevalence of Behҫet’s disease in the UK is estimated at 0.64 per 100,000 population, which equates to approximately 400 patients13. Approximately 50-70% of patients with Behҫet’s disease have uveitis3,12 and current estimates indicate that severe visual impairment occurs in 25% of involved eyes7.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

No relevant guidance identified.

Other Guidance

• NHS Clinical Knowledge Summary. Uveitis (version 1.1). 20091. • Lyon F, Gale RG and Lightman S. Recent developments in the treatment of uveitis: an update. 200917. • Royal College of Ophthalmologists. Guidelines for Intravitreal Injections Procedure. 200918. • McCluskey PJ, Towler HMA and Lightman S. Management of Chronic Uveitis. 20004.

a BCVA: Best-corrected visual acuity.

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• Consensus Panel on Immunosuppression for Ocular Disease. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. 200019.

EXISTING COMPARATORS and TREATMENTS

Corticosteroids are the mainstay of treatment for sight threatening posterior uveitis usually by periocular and occasionally intraocular steroid injection. However this is associated with significant systemic and ocular complications (such as glaucoma or cataract) if used at high doses over the longer term12,16. Consequently, other immunosuppressive ‘corticosteroid sparing’ therapies may be used in an effort to reduce the corticosteroid dose required.

Current treatment options for non-infectious uveitis include10,13,17,20 : • Cyclopegics eye drops – e.g. cyclopentolate or atropine sulphate. • Corticosteroids: o Topical preparations – e.g. dexamethasone, prednisolone, rimexolone eye drops or fluorometholone eye drops (used in anterior uveitis). o Intravitreal injections – e.g. dexamethasone (used [rarely] in posterior uveitis), triamcinolone (unlicensed for this indication). o Intravitreal implant – e.g. dexamethasone (used in non-infectious posterior uveitis). o Systemic therapy – e.g. oral prednisolone or parenteral therapy (used in bilateral and/or severe cases of posterior or intermediate uveitis). • Non-steroidal anti-inflammatory drugs (NSAIDs, not licensed for this indication in the UK) – e.g. diclofenac eye drops. • Immunosuppressive drugs (not licensed for this indication in the UK): o Antimetabolites – e.g. azathioprine, mycophenolate mofetil (or mycophenolic acid) or methotrexate. o Leukocyte signalling inhibitors – e.g. ciclosporin or tacrolimus. o Tumour necrosis factor (TNF)-α inhibitors – e.g. , or are considered in patients who fail to respond to one or two ‘classic’ immunosuppressive agents (such as antimetabolites) or leukocyte signalling inhibitorsb. o Alkylating agents – e.g. cyclophosphamide or chlorambucil (used for severe vision- threatening conditions).

EFFICACY and SAFETY

Trial EYEGUARD™-A, EYEGUARD™-C, EYEGUARD™ B, NCT01684345; NCT01747538; EudraCT Number: 2012- gevokizumab vs placebo; gevokizumab vs placebo; 001125-27; gevokizumab phase III. phase III. vs placebo; phase III. Sponsor Xoma (US) LLC. Xoma (US) LLC. Servier. Status Ongoing. Ongoing. Ongoing. Source of Trial registry21. Trial registry22. Trial registry23. information Location USA only. USA only. EU (inc UK), and other countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled.

b Expert clinical opinion.

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Participants n=300 (planned); aged n=300 (planned); aged ≥18 n=80 (planned); aged ≥18 ≥18 years; diagnosis of years; diagnosis of non- years; diagnosed with non-infectious infectious intermediate, Behҫet’s disease intermediate, posterior, or posterior, or pan-uveitis in associated uveitis with pan-uveitis in at least one at least one eye; ocular involvement of the eye; active uveitic disease controlled uveitic disease posterior segment; stable in at least one eye; on at in both eyes; on stable background treatment least one of the following dose of oral corticosteroids regimen of oral stable treatment regimens: in combination with corticosteroid and oral corticosteroids, selected immunosuppressive systemic immunosuppressive treatment; without severe immunosuppressant therapy. cataract or severe . posterior capsular opacification. Schedule Not reported by company. Not reported by company. Not reported by company. Follow-up Not reported by company. Not reported by company. Not reported by company. Primary Responders at day 56. Occurrence of uveitic Time to first ocular outcome/s disease to day 168. exacerbation. Secondary Not reported. Quality of life Time to first occurrence of Ocular exacerbations; outcome/s measurements not uveitic disease. Quality of visual acuity. Quality of life reported by company. life measurements not measurements not reported by company. reported by company. Expected Estimated study Estimated study completion Estimated study reporting completion date Sept date Feb 2015. completion date Sept date 2015. 2016.

Trial ISRCTN15180871; gevokizumab; phase II. Sponsor Servier. Status Ongoing. Source of Trial registry24, manufacturer. information Location South Korea, Tunisia and Turkey. Design Randomised, open-label. Participants n=21 (planned); aged 18 to 80 years; patients with uveitis associated with Behҫet’s disease; stable regimen of oral corticosteroids and immunosuppressive treatment; without severe cataract. Schedule Not reported by company. Follow-up Active treatment for 1 year. Primary Safety (adverse events (AEs); vital signs; laboratory values; ECG and X-ray). outcome/s Secondary Pharmokinetics; opthalmological assessments. Quality of life measurements not outcome/s reported by company. Expected Estimated study completion date May 2013. reporting date

ESTIMATED COST and IMPACT

COST

The cost of gevokizumab for this indication is not yet known. The cost of a single 700µg dexamethasone intravitreal implant (Ozurdex) is £87025. However this figure does not include of the cost of the surgical implantation.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services: by comparison with Ozurdex where a surgical procedure is needed to place and remove the implant. However, use of gevokizumab will require increased monitoring of patients for as long as they are on this drug, including blood or other tests at regular intervals. At present, this is undertaken by nursing staff trained in immunosuppression in rheumatology, or less often, ophthalmology departmentsc.

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other: uncertain unit cost compared to  None identified existing treatments.

Other Issues

 Clinical uncertainty or other research question  None identified identified: There are currently no effective ways of predicting severity, and therefore outcome of disease in chronic, non-infectious uveitis. Further research in this area would be useful. In addition, the increased use of intravitreal therapies requires the rigour of randomised trials in order to describe their place in treatment. This is important as the local side-effects of intravitreal treatment (eg, cataract/glaucoma) are relatively easy to manage, whereas the long-term side effects from systemic immunosuppression are more difficult, particularly for ophthalmologistsc.

REFERENCES

1 Clinical Knowledge Summaries. Uveitis. Version 1.1. November 2009. http://www.cks.nhs.uk 2 Jabs DA, Nussenblatt RB and Rosenbaum JT. Standardisation of uveitis nomenclature for reporting clinical data. Results of the first international workshop. American Journal of Ophthalmology 2005;140:509-516.

c Expert clinical opinion.

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3 Patient.co.uk. Uveitis and Iritis. http://www.patient.co.uk/health/Uveitis-and-Iritis.htm Accessed 22 April 2013. 4 McCluskey PJ,Towler HMA and Lightman S. Management of chronic uveitis. BMJ 2000;320:555- 558. 5 Munoz-Fernandez S and Martin-Mola E. Uveitis. Best Practice and Research Clinical Rheumatology 2006;20:487-505. 6 Clinical Knowledge Summary Clinical Topic – Uveitis http://www.cks.nhs.uk/uveitis Accessed 19 April 2013. 7 Behҫet’s Syndrome Society. The eye in Behçet’s disease. http://www.behcets.org.uk/Documents/web%20-%20eyes.pdf Accessed 23 April 2013. 8 Wakefield D and Chang JH. Epidemiology of uveitis. International Ophthalmology Clinic. 2005;45(2):1-13. 9 Kim EC and Foster CS. Immunomodulatory therapy for the treatment of ocular inflammatory disease: evidence-based medicine recommendations for use. International Ophthalmology Clinic. 2006;46(2):141-64. 10 NIHR Horizon Scanning Centre. Intravitreal sirolimus (Opsiria) for chronic non-infectious posterior segment uveitis – first or second line. University of Birmingham, January 2013. http://www.hsc.nihr.ac.uk 11 Saari KM, Päivönsalo-Hietanen T, Vaahtoranta-Lehtonen H et al. Epidemiology of endogenous uveitis in south-western Finland. Acta ophthalmologica Scandinavica 1995;73(4):345-9. 12 NHS Choices. Health A-Z: conditions. Uveitis. April 2013. http://www.nhs.uk/conditions/Uveitis Accessed 22 April 2013. 13 Sakane T, Takeno M, Suzuki N et al. Behҫet’s Disease. New England Journal of Medicine 1999;341:1284-91. 14 O'Shea J, Infeld D and Harvey R. Uveitis- a photoessay. http://medweb.bham.ac.uk/easdec/eyetextbook/Uveitis/uveitis.htm Accessed 22 April 2013. 15 Gritz DC and Wong IG. Incidence and prevalence of uveitis in Northern California: The Northern California Epidemiology of Uveitis Study. Ophthalmology 2004;111(3):491-500. 16 North East Treatment Advisory Group. Ozurdex dexamethasone ocular implant for uveitis. January 2011. http://www.nyrdtc.nhs.uk/docs/eva/NETAG%20appraisal%20report%20- %20Ozurdex%20for%20uveitis%20-Jan2012.pdf 17 Lyon F, Gale RG and Lightman S. Recent developments in the treatment of uveitis: an update. Expert Opinion on Investigational Drugs 2009;18:609-616. 18 The Royal College of Ophthalmologists. Guidelines for intravitreal injections procedure. London: Royal College of Ophthalmologists; 2009. www.rcophth.ac.uk 19 Jabs DA, Rosenbaum JT, Foster CS et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. American Journal of Ophthalmology 2000;130(4):492-513. 20 Cunningham ET. New drugs and innovative drug delivery systems will pave the way for future treatments in uveitis. Retina Today November/December 2012:65-74. http://bmctoday.net/retinatoday/pdfs/1112RT_Medical_Cunningham.pdf Accessed 24 April 2013. 21 ClinicalTrials.gov. Safety and efficacy study of gevokizumab to treat active non-infectious uveitis (EYEGUARD™-A). http://clinicaltrials.gov/ct2/show/NCT01684345 Accessed 22 April 2013. 22 ClinicalTrials.gov. Safety and efficacy study of gevokizumab to treat non-infectious uveitis controlled with systemic treatment (EYEGUARD™-C). http://clinicaltrials.gov/ct2/show/NCT01747538?term=NCT01747538&rank=1 Accessed 22 April 2013. 23 Clinicaltrialsregister.eu. A randomised, double-masked, placebo-controlled study of the efficacy of gevokizumab in the treatment of patients with behҫet’s disease uveitis. https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-001125-27/GB Accessed 23 April 2013. 24 Controlled-trials.com. A study of gevokizumab in subjects with Behçet’s disease uveitis. http://www.controlled-trials.com/ISRCTN15180871/ Accessed 22 April 2013. 25 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 64. London: BMJ Group and RPS Publishing, March 2013.

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