Voclosporin for moderate to severe plaque psoriasis

December 2008

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

December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

Voclosporin for moderate to severe plaque psoriasis

Target group • Plaque psoriasis: moderate to severe - adults who fail to respond to, or have contraindication to, or are intolerant of other systemic therapies including psoralen ultraviolet A (PUVA), acitretin, , and biologics e.g. , , and .

Technology description Voclosporin (ISA-247) belongs to the inhibitor class of drugs. Voclosporin suppresses the immune response by reversibly inhibiting T-cell proliferation and the release of pro-inflammatory cytokines. Voclosporin is administered orally at a dosage of 0.4mg/kg twice daily. A periodic serum creatinine assessment may be necessary.

Voclosporin is also in phase III development for uveitis in the EU and in phase II development for the prevention of renal transplant rejection in Canada and the USA.

Innovation and/or advantages Voclosporin has the potential to be more potent and less toxic than ciclosporin.

Developer Isotechnika Inc.

Availability, launch or marketing dates, and licensing plans: In phase III clinical trials.

Relevant guidance NICE Technology Appraisals • NICE technology appraisal in development. for the treatment of moderate to severe psoriasis. Expected date to be confirmed1. • NICE technology appraisal. Adalimumab for the treatment of psoriasis. 20082. • NICE technology appraisal. Infliximab for the treatment of adults with psoriasis. 20083. • NICE technology appraisal. Etanercept and efalizumab for the treatment of adults with psoriasis. 20064.

NICE Clinical Guidelines • NICE intervention procedure guidance. Grenz rays therapy for inflammatory skin conditions. 20075.

• American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1 - overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. 20086. • Dermatology UK. Best practice in emollient therapy: a statement for healthcare professionals. Care guideline. 20077. • British Association of Dermatologists. Clinical guidelines - psoriasis. 20068. • British Association of Dermatologists. Guidelines for use of biological interventions in psoriasis. 20059.

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Clinical need and burden of disease Plaque psoriasis is a non-infectious, inflammatory disease of the skin characterised by raised red patches of skin (plaques) caused by increased epidermal proliferation. Plaques can occur anywhere on the body, but the most common sites are the elbows, knees and scalp. Plaque psoriasis is a chronic-progressive condition, but its course may be erratic, with flare-ups and remissions. The disease is disfiguring, stigmatising and associated with a significantly impaired quality of life. Plaque psoriasis has been shown to affect health- related quality of life (HRQoL) to an extent similar to the effects of other chronic diseases such as depression, myocardial infarction, hypertension, congestive heart failure or type 2 diabetes4.

It is estimated that psoriasis affects around 2% of the UK population and of these people 80% have chronic plaque psoriasis4. This equates to 817,472 people in England with chronic plaque psoriasis. Psoriasis can develop at any age, but onset is most common between the ages of 15 and 2510.

In England, in 2007, there were 1,137,700 prescription items dispensed for psoriasis with a net ingredient cost of £35,391,30011.

Existing comparators and treatments First-line therapies • Emollients, salicyclic acid, topical steroids, vitamin D analogues, coal tar, dithranol and tazarotene (a topical retinoid). Phototherapy • UVB or a psoralen/UVA combination. Systemic therapies • Acitretin, ciclosporin, methotrexate, adalimumab, efalizumab, etanercept and infliximab.

Efficacy and safety

Trial ISA-04-03, SPIRIT, NCT00244842: ISA-05-02, SPIRIT extension, voclosporin vs placebo; phase III. NCT00258713: voclosporin. Sponsor Isotechnika. Isotechnika. Status Published12. Abstract13. Location Canada. Canada. Design Randomised, double-blind, placebo Open label, extension study. controlled. Participants n=451; adults; plaque psoriasis involving n=296; previously enrolled in the and schedule ≥10% of the body surface area (BSA) for at SPIRIT study. least 6 months; psoriasis area and severity Patients given 0.3mg/kg voclosporin index (PASI) score of ≥10; glomerular twice daily for 36 weeks (additional to filtration rate (GFR) of >60ml/min. SPIRIT). Randomised to voclosporin 0.2mg/kg, 0.3mg/kg, 0.4mg/kg or placebo orally twice daily for 12 weeks. After 12 weeks patients on placebo received 0.3mg/kg voclosporin twice daily for 12 weeks. Patients on voclosporin continued in their treatment groups for a total of 24 weeks. Follow-up 24 weeks treatment; 12 weeks follow up. 36 weeks treatment (total of 60 weeks); 12 weeks follow up. Primary Improvement in PASI scores of 75% PASI75 3 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare outcome/s (PASI75) at 12 weeks. Secondary Static global assessment (SGA) score; 70% 2 point reduction in SGA score. outcomes reduction in BSA (BSA70); target site lesion assessment; 50% improvement in PASI (PASI50) score and 90% improvement in PASI (PASI90) score. Key results At week 12, significantly greater proportion Efficacy continued throughout of patients in the voclosporin 0·3mg/kg treatment. At week 60 29% of patients (p=0·0085) and 0·4mg/kg (p<0·0001) groups had a 2 point reduction in SGA and achieved PASI75, than in the placebo group. 31% met PASI75. After study Voclosporin 0·3mg/kg and 0·4mg/kg resulted conclusion 79% of patients did not in significantly (p=0·0016 and p<0·0001, have a return of their disease. Only 7% respectively) greater reduction in SGA scores of patients experienced a psoriatic than placebo. Voclosporin 0·3mg/kg and flare during the 12 week follow-up. 0·4mg/kg showed greater success rates than placebo with other secondary endpoints including BSA70, PASI50, PASI90 and most of the quality of life (QoL) scores. From 12- 24 weeks, patients in the voclosporin 0·3mg/kg and 0·4mg/kg groups maintained their PASI75, SGA, PASI50 and BSA70 scores. Patients in the placebo group given voclosporin 0·3mg/kg from week 12 onwards had a clinically significant improvement in PASI75, SGA, and BSA70 scores at week 24. Adverse Adverse events were reported by 82% of Treatment related adverse events effects patients. About half of voclosporin treated reported in ≥2% of patients were: patients had adverse events that were thought hypertension (10.8%), nasopharyngitis to be treatment-related, compared with 39% (3%), exacerbation of hypertension of the placebo group. Headache, (3.4%), headache (2%) and nausea nasopharyngitis, and upper-respiratory-tract (1.7%). infections were the most frequently reported adverse events. Mild to moderate GFR reductions were seen in eight (2%) patients during the study.

Trial ISA01-02: voclosporin vs placebo; phase II. Sponsor Isotechnika. Status Published14,15. Location Canada. Design Randomised, double-blind, placebo controlled. Participants n=201; adults; plaque psoriasis for at least 6 months previously; ≥10% BSA. and schedule Randomised to voclosporin 0.5mg/kg, 1.5mg/kg or placebo daily for 12 weeks.

Follow-up 12 weeks treatment, 6 weeks follow up. Primary 2 point reduction in SGA score. outcome/s Secondary PASI75; target site lesion assessment; BSA. DLQI (dermatology life quality index); outcomes PDI (psoriasis disability index). Key results The proportion of patients with a 2-point reduction in the SGA score at week 12 was 15.6% with voclosporin 0.5 mg/kg, 45.1% with voclosporin 1.5 mg/kg and 0% with placebo (p < .0001 for both active treatment groups). The mean percentage change in the PASI score showed dose-dependent decreases from baseline. At 12 weeks, PASI75 was 0% with placebo, 18% with voclosporin 0.5 mg/kg and 67% with voclosporin 1.5 mg/kg (p < .0001).

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Adverse The most commonly reported adverse events classified as drug-related: nausea, effects headache and abnormal chemistry changes.

Trial ISA-05-25; ESSENCE; NCT00408187: voclosporin vs ciclosporin or placebo; phase III. Sponsor Isotechnika. Status Ongoing16. Location Canada, Germany, Poland. Design Randomised, double-blind, placebo controlled. Participants and n=642; adults. schedule Randomised 3:1:1 to voclosporin 0.4mg/kg, ciclosporin 1.5mg/kg or placebo twice daily for a total of 60 weeks. At week 12 patients receiving placebo will be changed to voclosporin 0.4mg/kg twice daily for 48 weeks. Follow-up 12 weeks. Primary Achievement of clear or almost clear in the SPGA scores at 12 weeks. outcome/s Secondary Safety/adverse events; SPGA; PASI and lattice system physicians global outcomes assessment (LS-PGA); PDI; DLQI. Estimated study December 2008. completion date

Estimated cost and cost impact The cost of voclosporin is yet to be determined. The need for a periodic serum creatinine assessment would add additional costs.

The cost of currently available systemic therapies is as followsa, 17:

Drug Dose Cost (3 months treatment) Acitretin Initially 25-30mg for 2-4 weeks then 25-50mg. £146 (Neotigason) Ciclosporin 2.5-5mg/kg. £284-£567 (Neoral) Methotrexate 25mg once a week. £15 Adalimumab Initially 80mg SC; then 40mg SC alternate weeks. £2,860 (Humira) Efalizumab Initially 0.7mg/kg SC; then 1mg/kg SC weekly. £1,070 (Raptiva) Etanercept (Enbrel) 25mg SC twice a week. £2,145 Infliximab 5mg/kg IV initially, repeated at 2 and 6 weeks, and £2,301 (Remicade) then every 8 weeks.

Potential or intended impact – speculative

Patients ; Reduced morbidity: decreased Reduced mortality or increased ; Improved quality of life for nephrotoxicity18. length of survival patients and/or carers

Quicker, earlier or more accurate Other: None identified diagnosis or identification of disease

a Based on an average weight of 67.5kg. 5 December 2008 National Horizon Scanning Centre News on emerging technologies in healthcare

Services ; Increased use: additional Service reorganisation required Staff or training required treatment.

; Decreased use: fewer periodic Other: None identified serum creatinine assessments compared to ciclosporin.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: Additional drug costs Savings: Other: and potential serum creatinine assessment.

References

1National Institute for Health and Clinical Excellence. Ustekinumab for the treatment of moderate to severe psoriasis. Technology appraisal in development. Issue date to be confirmed. 2National Institute for Health and Clinical Excellence. Adalimumab for the treatment of psoriasis. Technology appraisal 146. June 2008. 3National Institute for Health and Clinical Excellence. Infliximab for the treatment of adults with psoriasis. Technology appraisal 134. January 2008. 4National Institute for Health and Clinical Excellence. Etanercept and efalizumab for the treatment of adults with psoriasis. Technology appraisal 103. July 2006. 5National Institute for Health and Clinical Excellence. Grenz rays therapy for inflammatory skin conditions. Intervention procedure guidance 236. November 2007. 6American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1 - Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. May 2008. http://www.aad.org/research/_doc/Psosection1.pdf Accessed 10/11/08. 7Dermatology UK. Best practice in emollient therapy: a statement for healthcare professionals. Care Guideline. November 2007. http://www.dermatology-uk.com/downloads/Emollient_Therapy_BP.pdf Accessed 10/11/08. 8British Association of Dermatologists. Clinical guidelines - psoriasis. 2006. http://www.bad.org.uk/healthcare/guidelines/psorsites.asp Accessed 20/03/08. 9British Association of Dermatologists. Guidelines for use of biological interventions in psoriasis. British Journal of Dermatology 2005; 153 (3): 486-497. 10Patient UK. Psoriasis. http://www.patient.co.uk/printer.asp?doc=23068811 Accessed 14/03/08. 11The Information Centre, Prescribing Support Unit. Prescription cost analysis data. 2008. 12Papp, K., Bissonnette R., Rosoph, L. et al. Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double-blind, placebo controlled phase III study. The Lancet 2008; 371; 1337-1342. 13Gulliver, W., Bissonnette R., Kunynetz, R. et al. ISA247 well tolerated after 60 weeks of continuous therapy. Abstract 1211 presented at the 21st World Congress of Dermatology. October 1-5, 2007, Buenos Aires, Argentina. 14Bisonette, R., Papp K., Poulin Y. et al. A randomised, multicentre, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. Journal of the American Academy of Dermatology 2006; 54; 3; 472-478. 15Gupta, A., Langley, R., Lynde, C. et al. ISA247: Quality of life results from a phase II, randomised, placebo controlled study. Journal of Cutaneous Medicine and Surgery 2008; 12; 1-9. 16Sterry, W., Gulliver W., Ho V. et al. The essence study a positive and placebo controlled, double blind, multicentre study of ISA247 in moderate to severe plaque psoriasis. Abstract presented at the 21st world congress of dermatology. Oct 1-5, 2007, Buenos Aires, Argentina. 17British Medical Association. British National Formulary 55. London: BMA September 2008. 18Griffiths CEM et al., British Journal of Dermatology 2004; 150; 67; 11-23.

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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 those of the author and 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, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon

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