Dimethyl Fumarate

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

Dimethyl fumarate for plaque

psoriasis SUMMARY NIHR HSC ID: 7758 Dimethyl fumarate is intended to be used for the treatment of moderate to severe plaque psoriasis. If licensed dimethyl fumarate may present an additional treatment option for this patient group, potentially delaying or avoiding the need for biological therapies. Dimethyl fumarate is one of three fumaric acid salts present in Fumaderm, a drug already licensed in Germany for plaque psoriasis. Plaque psoriasis is the most common type of psoriasis, representing 90% of cases. The estimated UK prevalence of psoriasis is 1.5-1.63%, with 1.1% of suffering with severe disease. It has a bimodal onset, with the first peak occurring in persons aged 16 to 22 years, and the second in persons aged 57 to 60 years. The prevalence of psoriasis in those younger than 10 years is estimated to be 0.55% and 1.4% in those aged between 10 and 19 years. The estimated prevalence of people currently eligible for biological therapy in England is 1.1% of those with psoriasis. Chronic plaque psoriasis is typified by itchy, well demarcated circular-to-oval bright red/pink elevated lesions (plaques) with overlying white or silvery scale, distributed symmetrically over extensor body surfaces and the scalp. Current treatment options include topical ointments and emollients, phototherapy, systemic therapies (e.g. oral retinoids) and biological therapies. Dimethyl fumarate is currently in a phase III clinical trial comparing its effect on psoriasis area and severity index (PASI) against treatment with Fumaderm or placebo. This trial is expected to complete in December 2014.

Horizon Scanning Centre November 2013

This briefing 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 or commissioning without additional information.

NIHR Horizon Scanning Centre

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TARGET GROUP Plaque psoriasis: moderate to severe. TECHNOLOGY DESCRIPTION Dimethyl fumarate (LAS-41008) is a methyl ester of fumaric acid. Fumaric acid and its sodium salts have been previously used in psoriasis, and dimethyl fumarate appears to be the most active compound when given orally. Dimethyl fumarate inhibits certain functions of endothelial cells, namely, differentiation, proliferation and migration, as well as affecting the immune system and proliferating cells in general. Dimethyl fumarate is administered at a starting dose of 30mg daily, titrated up to a maximum of 720mg daily. Dimethyl fumarate is also in development for multiple sclerosis. It is also one of three fumaric acid salts present in Fumaderm, which is currently licensed for the treatment of plaque psoriasis in Germany. INNOVATION and/or ADVANTAGES If licensed dimethyl fumarate may present an additional treatment option for this patient group, potentially delaying or avoiding the need for biological therapies. DEVELOPER Almirall SA. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Psoriasis is defined as a chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations1. It is characterised by scaly skin lesions, which can be in the form of patches, papules, or plaques. The skin lesions of psoriasis are characterised by1: Hyperproliferation of the epidermis. Dilation and proliferation of blood vessels in the dermis. Accumulation of inflammatory cells, particularly neutrophils and T-lymphocytes. Chronic plaque psoriasis is typified by itchy, well demarcated circular-to-oval bright red/pink elevated lesions (plaques) with overlying white or silvery scale, distributed symmetrically over extensor body surfaces and the scalp2. Plaque psoriasis may manifest differently in children plaques may not be as thick, and the lesions may be less scaly. Psoriasis may also appear in the flexural areas in children and the disease more commonly affects the face compared with adults3.


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NHS or GOVERNMENT PRIORITY AREA None identified. CLINICAL NEED and BURDEN OF DISEASE Plaque psoriasis is the most common type of psoriasis, representing 90% of cases. The estimated UK prevalence of psoriasis is 1.5-1.63%4,5, with 1.1% of people suffering with severe disease5. It has a bimodal onset, with the first peak occurring in persons aged 16 to 22 years, and the second in persons aged 57 to 60 years. The prevalence of psoriasis in those younger than 10 years is estimated to be 0.55% and 1.4% in those aged between 10 and 19 years4,6. The estimated prevalence of people currently eligible for biological therapy in England is 1.1% of those with psoriasis5. Females typically develop plaque psoriasis earlier than males, and patients with a positive family history for psoriasis also tend to have an earlier age of onset4. Acute flares or relapses of plaque psoriasis may evolve into more severe disease, such as pustular or erythrodermic psoriasis7. The significant reduction in quality of life and psychosocial disability suffered by people with psoriasis underlies the need for prompt, effective treatment, and long-term disease control8. In 2011-12, for all age groups there were 13,546 hospital admissions due to psoriasis in England, equating to 14,094 finished consultant episodes and 23,195 bed days. There were a total of 356 finished consultant episodes for patients aged up to 14 years in 2011-129. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal. Ustekinumab for the treatment of adults with moderate to

severe psoriasis (TA180). September 200910. NICE technology appraisal. Adalimumab for the treatment of adults with psoriasis

(TA146). June 200811. NICE technology appraisal. Infliximab for the treatment of adults with psoriasis (TA134).

January 200812. NICE technology appraisal. Etanercept and efalizumab for the treatment of adults with

psoriasis (TA103). July 200613.

NICE clinical guideline. Psoriasis: the assessment and management of psoriasis (CG153). October 201214.

Other Guidance The Canadian Guidelines for the Management of Plaque Psoriasis. Consensus

guidelines for the management of plaque psoriasis. 201215. American Academy of Dermatology. Guidelines of care for the management of psoriasis

and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: Case-based presentations and evidence-based conclusions. 20111.

SIGN. Diagnosis and management of psoriasis and psoriatic arthritis in adults. 201016. British Association of Dermatologists and Primary Care Dermatology Society. Clinical

guideline: Recommendations for the initial management of psoriasis. 200917.


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British Association of Dermatologists' guidelines for biologic interventions for psoriasis. 200918.

American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. 200919.

Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. 200920.

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. 20087.

EXISTING COMPARATORS and TREATMENTS Current treatment options for plaque psoriasis include,15,18,21,22:

Topical (alone or in combination) Emollients.

Corticosteroids: betamethasone dipropionate. Vitamin D analogues: calcipotriol, calcitriol, tacalcitol and tazarotene (with or without

phototherapy). Tars (with or without phototherapy). Dithranol (with or without phototherapy). Retinoids: tazarotene. Salicyclic acid. Tacrolimus ointment (not licensed for this indication).

Phototherapy

Narrow band UVB and psoralen and UVA combination (PUVA).

Systemic therapies (for the treatment of patients with severe or refractory psoriasis) Oral retinoids: acitretin (with or without phototherapy). Hydroxycarbamide (not licensed for this indication). Fumaric acid esters: monoethylfumarate and dimethylfumarate (licensed in the EU but

not in the UK). Ciclosporin. Methotrexate.

Biologics (for the treatment of patients intolerant, contraindicated or refractory to other treatments) Drugs affecting the immune response: adalimumab, etanercept, infliximab, and ustekinumab. EFFICACY and SAFETY Trial NCT01726933, M41008-1102, 2012-000055-13; dimethyl fumarate or Fumaderm vs

placebo; phase III. Sponsor Almirall SA. Status Ongoing. Source of information

Trial registry23.

Location EU (not incl UK).


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Design Randomised, placebo-controlled. Participants n=690 (planned); 18 years; moderate to severe plaque psoriasis. Schedule Randomised to oral dimethyl fumarate, at a starting dose of 30mg daily, titrated up to a

maximum of 720mg daily, Fumaderm (dose not reported) or placebo. Follow-up Active treatment period 6 weeks, follow-up 12 months thereafter. Primary outcome/s

Psoriasis area and severity index (PASI) 75; physician global assessment (PGA).

Secondary outcome/s

Body surface area; dermatological life quality index; PASI 75 at week 3, 8 and follow-up; PGA at week 3, 8 and follow-up; adverse events.

Expected reporting date

Estimated study completion date Dec 2014.

ESTIMATED COST and IMPACT COST The cost of dimethyl fumarate is not yet known. The costs of other selected treatments for severe plaque psoriasis are given below22: Drug Dosea Unit Cost Annual cost Adalimumab (Humira)

80mg SC; then 40mg SC on alternate weeks one week after initial dose.

352 (40mg, prefilled syringe)

9,504

Etanercept (Enbrel)

25mg SC twice weekly or 50mg SC once weekly.


9,256

Infliximab (Remicade)

5mg/kg IV repeated at 2 and 6 weeks; then every 8 weeks.

420 (100mg vial) 11,760

Ustekinumab (Stelara)

Initially 45mg, then 45mg 4 weeks after initial dose, then 45mg every 12 weeks.


10,735

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: oral treatment option. Fumaderm is also currently used off-licence in most UK departments to control chronic plaque psoriasis. This may negate the need for specialist training in order to initiate and prescribe this therapyb.

Re-organisation of existing services Need for new services

Other None identified

a Based on an average body weight of 77.9kg. b Expert personal communication.


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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 existing treatments.

None identified

Other Issues

Clinical uncertainty or other research question identified: Expert opinion suggests it would be beneficial to have more data on the efficacy of dimethyl fumarate in a paediatric population and to determine how immunosuppressive the therapy is in relation to other systemic agents for plaque psoriasis (e.g. methotrexate). There are also a number of other oral drugs in development for plaque psoriasisc.

None identified

REFERENCES 1 American Academy of Dermatology. Guidelines of care for the management of psoriasis and

psoriatic arthritis: Section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. Journal of the American Academy of Dermatology 2011;65(1):137-74.

2 Patient.co.uk. Chronic Plaque Psoriasis. October 2011. http://www.patient.co.uk/doctor/chronic-plaque-psoriasis.htm Accessed 16 April 2013.

3 Lui H and Mamelak AJ. Plaque Psoriasis. Medscape reference: Drugs, diseases and procedures. March 2011. http://emedicine.medscape.com/article/1108072-overview Accessed 8 September 2013.

4 Gelfand JM, Weinstein R, Porter SB et al. Prevalence and treatment of psoriasis in the United Kingdom: a population-based study. Archives of Dermatology 2005;141(12):1537-41.

5 National Institute for Health and Clinical Excellence. Costing statement: ustekinumab for the treatment of adults with moderate to severe psoriasis. London: NICE; September 2009. http://www.nice.org.uk/nicemedia/live/12235/45509/45509.pdf

6 Chaplin S and Atherton D. Etanercept: a new option in paediatric plaque psoriasis. Future Prescriber 2009;9(3):6-10.

7 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. Journal of the American Academy of Dermatology 2008;58(5):826-50.

8 NIHR Horizon Scanning Centre. Tofacitinib for moderate to severe chronic plaque psoriasis second line. University of Birmingham, November 2012. http://www.hsc.nihr.ac.uk

9 NHS Hospital episode statistics. NHS England 2011-12 HES data. 2012. www.hesonline.nhs.uk 10 National Institute for Health and Clinical Excellence. Ustekinumab for the treatment of adults with

moderate to severe psoriasis. Technology Appraisal TA180. London: NICE; September 2009. 11 National Institute for Health and Clinical Excellence. Adalimumab for the treatment of adults with

psoriasis. Technology appraisal TA146. London: NICE; June 2008. 12 National Institute for Health and Clinical Excellence. Infliximab for the treatment of adults with

psoriasis. Technology appraisal TA134. London: NICE; January 2008. 13 National Institute for Health and Clinical Excellence. Etanercept and efalizumab for the treatment of

adults with psoriasis Technology appraisal TA103. London: NICE; July 2006. 14 National Institute for Health and Clinical Excellence. Psoriasis: the assessment and management of

psoriasis. Clinical guideline CG153. London: NICE; October 2012 15 Hsu S, Papp KA, Lebwohl MG et al. Consensus guidelines for the management of plaque

psoriasis. Archives of Dermatology. 2012;148:95-102.

c Expert personal communication.


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16 Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic

arthritis in adults. National clinical guideline 121. Edinburgh: SIGN; October 2011. 17 British Association of Dermatologists & Primary Care Dermatology Society. Recommendations for

the initial management of psoriasis. October 2009. http://www.bad.org.uk/Portals/_Bad/Guidelines/Clinical%20Guidelines/BAD-PCDS%20Psoriasis%20reviewed%202010.pdf Accessed 9 September 2013.

18 Smith CH, Anstey AV, Barker JN et al. British Association of Dermatologists' guidelines for biologic interventions for psoriasis 2009. British Journal of Dermatology 2009;161(5):987-1019.

19 American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology 2009;61(3):451-85.

20 Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European Academy of Dermatology and Venereology 2009;23 Suppl 2:1-70.

21 National Institute for Health and Clinical Excellence. Psoriasis: final scope. London: NICE; December 2010 http://www.nice.org.uk/nicemedia/live/12344/52350/52350.pdf

22 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 63. London: BMJ Group and RPS Publishing, March 2013.

23 ClinicalTrials.gov. LAS41008 in moderate to severe chronic plaque psoriasis. http://clinicaltrials.gov/show/NCT01726933 Accessed 9 September 2013.

This briefing 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 f...DESCRIPTIONINNOVATION and/or ADVANTAGESDEVELOPERAVAILABILITY, LAUNCH OR MARKETINGBACKGROUNDNHS or GOVERNMENT PRIORITY AREACLINICAL NEED and BURDEN OF DISEASERELEVANT GUIDANCEEXISTING COMPARATORS and TREATMENTSCOSTIMPACT - SPECULATIVE

Dimethyl Fumarate

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