Horizon Scanning Centre January Apremilast for psoriasis SUMMARY NIHR HSC ID: 2652

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1 Horizon Scanning Centre January 2013 Apremilast for psoriasis SUMMARY NIHR HSC ID: 2652 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. Apremilast is intended to be used as therapy for the treatment of moderateto-severe psoriasis in adults who have had an inadequate response, a contraindication, or are intolerant to other systemic therapies including ciclosporin, methotrexate and psoralen with UVA treatment. If licensed, it will provide an additional treatment option for this patient group. Apremilast is a small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE- 4). The prevalence of psoriasis in England is estimated to be around 1.63% (644,000), of whom approximately 20% (129,000) have moderate to severe disease. Plaque psoriasis is the most common form, affecting 80-90% of people with the disease. The visible nature of psoriasis can create a sense of stigmatisation amongst those affected and the negative impact on healthrelated quality of life is comparable to that of ischaemic heart disease, diabetes, depression and cancer. Psoriasis is associated with considerable morbidity and an increased incidence of metabolic syndrome, heart disease, Crohn s disease, lymphoma, obesity and type 2 diabetes. Current treatment options include topical treatments, phototherapy, systemic therapies (for severe or refractory disease) and biologics (for patients intolerant, contraindicated or refractory to other treatments). Apremilast is currently in phase III clinical trials comparing its effect on psoriasis severity against treatment with etanercept and placebo. These trials are expected to report in 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 nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Psoriasis: moderate to severe - in adults who have had an inadequate response, or a contraindication, or are intolerant to other systemic therapies, including ciclosporin, methotrexate and psoralen with UVA treatment (PUVA). TECHNOLOGY DESCRIPTION Apremilast (CC-10004) is a small molecule inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4) that subsequently down-regulates the production of multiple pro-inflammatory mediators including interleukin-2 (IL02), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and nitric oxide synthase (NOS). In clinical trials, apremilast was administered orally at 30mg twice daily 1. Apremilast is in phase III clinical trials for ankylosing spondylitis and psoriatic arthritis, and in phase II trials for Behcet s syndrome. INNOVATION and/or ADVANTAGES If licensed, apremilast will provide an additional treatment option for this patient group. DEVELOPER Celgene. 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 manifestations 2. It typically follows a relapsing and remitting course 3 and is characterised by thickened, red, scaly skin lesions in the form of patches, papules, or plaques which arise due to 4 : Hyperproliferation of the epidermis. Dilation and proliferation of blood vessels in the dermis. Accumulation of inflammatory cells, particularly neutrophils and T-lymphocytes. The visible nature of psoriasis can create a sense of stigmatisation amongst those affected and the negative impact on health-related quality of life is comparable to that of ischaemic heart disease, diabetes, depression and cancer 5. 2

3 NHS or GOVERNMENT PRIORITY AREA This topic is relevant to The National Service Framework for Long-term Conditions (2005). CLINICAL NEED and BURDEN OF DISEASE The estimated prevalence of psoriasis in England is around 1.63% (644,000) 6, of whom approximately 20% (129,000) have moderate to severe disease 2. Plaque psoriasis is the most common form, affecting 80-90% of people with psoriasis 2. Onset may occur at any age but peaks in the second and third decades of life 5. Acute flares or relapses of plaque psoriasis may evolve into more severe disease, such as pustular or erythrodermic psoriasis and up to 10-20% of people with plaque psoriasis also experience psoriatic arthritis 7. Psoriasis is associated with considerable morbidity, with metabolic syndrome and heart disease causing the greatest increase in mortality a. Psoriasis is also associated with an increased incidence of Crohn s disease, lymphoma, obesity and type 2 diabetes 2. Life expectancy in men and women with severe psoriasis is reduced by 3.5 and 4.4 years respectively 5. In , there were 13,456 hospital admissions for psoriasis (ICD10 L40) in England, accounting for 14,094 finished consultant episodes and 23,195 bed days 8 and in 2011, 34 deaths were registered in England and Wales 9. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal. Ustekinumab for the treatment of adults with moderate to severe psoriasis (TA180). September NICE technology appraisal. Adalimumab for the treatment of adults with psoriasis (TA146). June NICE technology appraisal. Infliximab for the treatment of adults with psoriasis (TA134). January NICE technology appraisal. Etanercept and efalizumab for the treatment of adults with psoriasis (TA103). July NICE clinical guideline. Psoriasis: The assessment and management of psoriasis (CG153). October NICE quality standard in development. Psoriasis. Expected Autumn NICE interventional procedure guidance. Grenz rays therapy for inflammatory skin conditions (IPG236). November Other Guidance The Canadian Guidelines for the Management of Plaque Psoriasis. Consensus guidelines for the management of plaque psoriasis 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 SIGN. Diagnosis and management of psoriasis and psoriatic arthritis in adults a Expert personal communication. 3

4 British Association of Dermatologists and Primary Care Dermatology Society. Clinical guideline: Recommendations for the initial management of psoriasis British Association of Dermatologists' guidelines for biologic interventions for psoriasis 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 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 EXISTING COMPARATORS and TREATMENTS Current treatment options for plaque psoriasis include 14,23,24,25,b : Topical (alone or in combination) 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). Salicyclic acid. Tacrolimus ointment (not licensed for this indication). Phototherapy Narrow band UVB or 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). Drugs affecting the immune response: ciclosporin, methotrexate, azathioprine and mycophenolate mofetil. Biologics (for the treatment of patients intolerant, contraindicated or refractory to other treatments) 26 Drugs affecting the immune response: Anti-tumour necrosis factor: etanercept, infliximab and adalimumab. Anti-interleukin 12/23: ustekinumab. EFFICACY and SAFETY Trial NCT , CC PSOR-010, ; apremilast vs etanercept vs placebo; phase III. ESTEEM 1, NCT , CC PSOR-008; apremilast vs placebo; phase III. ESTEEM 2, NCT , CC PSOR-009; apremilast vs placebo; phase III. Sponsor Celgene Corporation. Celgene Corporation. Celgene Corporation. Status Ongoing. Ongoing. Ongoing. b Expert personal communication. 4

5 Source of information Trial registry 27, manufacturer. Trial registry 28, manufacturer. Location EU, USA and Canada. EU (inc UK), USA and Canada. Design Randomised, active- and Randomised, placebocontrolled. placebo-controlled. Participants n=240 (planned); aged 18 n=844 (planned); aged 18 years and older; plaque years and older; plaque psoriasis; chronic, psoriasis; chronic, moderate to severe; moderate to severe. inadequate response, intolerance, or contraindication to 1 systemic agent for psoriasis; no previous biologic treatment. Schedule Randomised to apremilast, oral, 30mg twice daily with placebo, subcutaneous injection (SC) once weekly; or etanercept, SC, 50mg once weekly with placebo, oral, twice daily; or placebo, oral, twice daily with placebo, SC once weekly. At week 16, all participants receive apremilast for remainder of 2 yr trial. Follow-up Active treatment period 2 yrs. Placebo controlled phase: randomised to apremilast, oral, 30mg twice daily, or placebo. Maintenance phase: placebo group switched to receive apremilast, oral, 30mg twice daily. Participants maintain this dose to week 32. Randomised withdrawal phase: At week 32, responders re-randomised to maintain apremilast, oral 30mg twice daily or placebo (treatment withdrawal). Upon relapse/lost response, treatment resumes with apremilast, oral, 30mg twice daily. For subjects originally randomised to placebo dosing at baseline, all participants maintain apremilast, oral, 30mg twice daily. Follow-up up to 4 yrs. Trial registry 29, manufacturer. EU, USA and Canada. Randomised, placebocontrolled. n=413 (planned); aged 18 years and older; plaque psoriasis; chronic, moderate to severe. Placebo controlled phase: randomised to apremilast, oral, 30mg twice daily, or placebo. Maintenance phase: placebo group switched to receive apremilast, oral, 30mg twice daily. Participants maintain this dose to week 32. Randomised withdrawal phase: for participants originally randomised to apremilast at baseline, responders re-randomised to maintain apremilast, oral, 30mg twice daily, or placebo (treatment withdrawal). Upon relapse/lost response, treatment resumes with apremilast, oral, 30mg twice daily. Participants originally randomised to placebo at baseline will maintain apremilast, oral, 30mg twice daily. Follow-up up to 4 yrs. Primary outcome Secondary outcomes PASI c score. PASI score. PASI score. Disease severity score; spga d ; change in affected body surface area (BSA); DLQI e ; SF-36 f ; LS-PGA g. spga; BSA; pruritus Visual Analogue Scale (VAS); psoriatic arthritis disease activity VAS; skin discomfort/pain VAS; spga; BSA; pruritus VAS; psoriatic arthritis disease activity VAS; skin discomfort/pain VAS; global assessment of psoriasis c PASI: Psoriasis Area and Severity Index. d spga: Static Physician s Global Assessment of overall disease severity. e DLQI: Dermatology Life Quality Index. f SF-36: 36-item Short-form Health Survey. g LS-PGA: Lattice System Physician s Global Assessment. 5

6 Expected reporting date gloval assessment of psoriasis disease activity VAS; DLQI; SF-36; PHQ- 8 h ; EQ-5D; WLQ-25 i ; clinically significant changes in physical examination, vital signs, electrocardiogram, clinical lab findings, psoriasis flare/rebound; pharmacokinetics. Q Q Q disease activity VAS; DLQI; SF-36; PHQ-8; EQ-5D; WLQ-25; clinically significant changes in physical examination, vital signs, electrocardiogram, clinical lab findings, psoriasis flare/rebound; pharmacodynamics. Trial NCT , CC PSOR-005; apremilast vs placebo; phase II. NCT , CC PSOR-005E; apremilast; phase II extension. NCT , CC PSOR-003; apremilast vs placebo; phase II. Sponsor Celgene Corporation. Celgene Corporation. Celgene Corporation. Status Published. Complete. Complete Source of information Publication 30, trial registry 31, manufacturer. Trial registry 32, manufacturer. Publication 33, trial registry 34, manufacturer. Location USA and Canada. USA and Canada. EU and Canada. Design Randomised, placebocontrolled. Non-randomised. Randomised, placebocontrolled. Participants n=352; aged 18 years and older; plaque psoriasis; chronic, moderate to severe. Schedule Randomised to apremilast, oral, 10mg, 20mg or 30mg twice daily, or placebo twice daily for 16 weeks followed by randomly assigned apremilast 20mg or 30mg twice daily. Follow-up Active treatment period 24 weeks; 4 weeks follow-up. n=209; aged 18 years and older; plaque psoriasis; chronic, moderate to severe; completed study NCT Participants continue same apremilast dose they were receiving at the end of the core study without interruption. Active treatment period 28 weeks; 4 weeks follow-up. n=260; aged 18 years and older; plaque psoriasis, moderate to severe. Randomised to apremilast, oral, 20mg once or twice daily, or placebo, oral, once or twice daily. Active treatment period 12 weeks; 4 weeks follow-up. Primary outcome Secondary outcomes Key results PASI score at week 16. Safety. Efficacy. spga; BSA; DLQI; SF-36; pruritus VAS; time to achieve PASI-50 or PASI- 75; vital signs; physical examination; lab findings; electrocardiograms; psoriasis flare; pharmacokinetics. For apremilast 10mg, 20mg, 30mg and placebo respectively (p value vs placebo): PASI-75 achieved at week Efficacy; PASI scores; BSA; spga; DLQI; SF-36. Safety; quality of life. - For apremilast 20mg once daily, twice daily and placebo respectively (p value vs placebo): PASI-75 achieved at week 12 (%), h PHQ-8: Patient Health Questionnaire. i WLQ-25: Work Limitations Questionnaire. 6

7 Adverse effects (AEs) Expected reporting date 16 (%),11 (p=0.19), 29 (p<0.0001), 41 (p<0.0001), 6; median time to PASI-75 (days), 70.0 (95% CI ), 83.0 (95% CI ), 44.0 (95% CI ), 57 (95% CI ); median time to PASI-50 (days), 41.0 (95% CI ), 42.0 (95% CI ), 30.0 (95% CI ), 45.5 (95% CI ); median time to PASI-90 (days), 50.5 (95% CI ), 87.0 (95% CI ), 58.0 (95% CI ), 57.0 (95% CI ); physicians global assessment score of 0 or 1 (%), 10, 24 (p=0.0425), 33 (p=0.0012),13; cleared or minimal disease at week 24 (%), 13, 24, 34 (placebo arm not reported); mean difference in DLQI score at week 16, -3.2, -5.9 (p<0.0001), -4.4 (p=0.0047), -1.9; clinically important improvement in DLQI score (%), 34, 49 (p=0.001), 44 (p=0.011), 25. AEs 5%, for apremilast 10mg, 20mg, 30mg and placebo respectively (%): nausea, 11, 15, 18, 8; upper respiratory tract infection, 10, 14, 16, 6; diarrhoea, 7, 7, 14, 5; nasopharyngitis, 10, 8, 6, 8; headache, 6, 9, 10, 6; tension headache, 3, 2, 16, 7; viral upper respiratory tract infection, 2, 8, 8, 8; gastroenteritis, 1, 5, 6, 3; dyspepsia, 1, 6, 5, 2; arthralgia, 1, 2, 2, 7; vomiting, 0, 3, 5, , 24.4 (p=0.023),10.3; PASI-50 achieved at week 12 (%), 27.6, 57.0 (p<0.001), 23.0; mean reduction in PAI score at week 12 (%), 30.3 (p=0.021), 52.1 (p<0.001), 17.4; relapse during followup (%), 24.2, 26.4, 21.7; mean change from baseline in overall spga at week 12, -0.8 (p=0.755), (p<0.001), -0.7; mean change from baseline in overall BSA, (p=1.104), (p<0.001), AEs >2%, for apremilast 20mg once daily, twice daily and placebo respectively (%): headache, 18.4, 12.9, 10.3; nasopharyngitis, 13.8, 14.1, 13.8; diarrhoea, 10.3, 5.9, 2.3; nausea, 3.4, 5.9, 0; vomiting, 2.3, 2.4, 0; upper abdominal pain, 2.3, 1.2, Q Q Trial NCT , CC PSOR-005LTE; apremilast vs placebo; phase II extension. NCT , CC PSOR-001; apremilast; phase II. NCT , CC PSOR-004; apremilast, phase II. Sponsor Celgene Corporation. Celgene Corporation. Celgene Corporation. Status Ongoing. Complete. Complete. 7

8 Source of Trial registry 35. Publication 36, trial Trial registry 38. information registry 37. Location USA and Canada. USA. USA. Design Non-randomised, placebocontrolled. Non-randomised, single arm. Non-randomised, single arm. Participants n=56 (planned); aged 18 years and older; plaque psoriasis; chronic; moderate to severe; completed study NCT n=19; aged years; plaque psoriasis; severe. n=31; aged 18 years and older; plaque psoriasis; chronic; inadequate response, intolerance or contraindication to 1 standard systemic therapy for psoriasis. Schedule Follow-up Primary outcomes Secondary outcomes Participants who received 20mg or 30mg twice daily in prior study continue to receive the same dose. Participants who received 10mg twice daily in prior study randomised to apremilast, 20mg or 30mg twice daily. Active treatment period up to 4 yrs; 4 weeks follow-up. AEs; long-term safety. PASI; BSA; spga; DLQI; SF-36. All participants received apremilast, oral, 20mg once daily. Active treatment period 29 days; 4 weeks follow-up. Pharmacodynamic effect in reducing epidermal thickness. PASI; spga; BSA. No quality of life measures included. Key results - 20% reduction in epidermal thickness, 53.3% (95% CI ); mean reduction in epidermal thickness from baseline to day 29, 20.5%; 50% reduction in PASI score, 17.6%. Adverse events (AEs) Expected reporting date All participants received apremilast, oral, 20mg twice daily. Nonresponders (based on PASI-75) were allowed to increase to apremilast, oral, 30mg twice daily, responders remained on apremilast, oral, 20mg twice daily. Active treatment period up to 24 weeks; 4 weeks follow-up. Safety and tolerability. Pharmacodynamic effects; PASI; quality of life % reported at least one AE; most common were headache (5 participants) and nausea (3 participants). - Not reported. - Not reported. - ESTIMATED COST and IMPACT COST The cost of apremilast is not yet known. The costs of selected treatments for plaque psoriasis are summarised below 39 : 8

9 Drug Dose Unit cost Adalimumab 80mg SC, then 40mg on alternate weeks starting one week after initial dose (40mg, prefilled syringe) Etanercept 25mg SC twice weekly or 50mg once (25mg, prefilled syringe) weekly. Infliximab 5mg/kg IV repeated at 2 and 6 weeks, then (100mg vial) every 8 weeks. Ustekinumab 45mg SC, then 45mg 4 weeks after initial dose, then 45mg every 12 weeks (45mg, prefilled syringe) 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 therapy 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 existing treatments None identified Other Issues Clinical uncertainty or other research question identified: clinical expert notes that current biologic agents are less effective for heavier patients at conventional doses, and is concerned to know whether dose adjustment will be required for these patients. REFERENCES None identified 1 ClinicalTrials.gov. A phase 3, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study of apremilast (CC-10004) in subjects with moderate to severe plaque psoriasis. Accessed 5 December Menter A, Korman NJ, Elmets CA et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Journal of the American Academy of Dermatology 2011;65(1) National Institute for Health and Clinical Excellence. Psoriasis: final scope. London: NICE; December Clinical Knowledge Summaries. Psoriasis background information. Accessed 5 November Scottish Intercollegiate Guidelines Network. Diagnosis and management of psoriasis and psoriatic arthritis in adults. National clinical guideline 121. Edinburgh: SIGN; October

10 6 National Institute for Health and Clinical Excellence. Adalimumab for the treatment of adults with psoriasis. Costing template and report. London: NICE; June Lui H and Mamelak AJ. Plaque Psoriasis. Medscape reference: Drugs, diseases and procedures. March Accessed October NHS Hospital episode statistics. NHS England HES data Office for National Statistics. Mortality statistics: deaths registered in 2011 (Series DR) Table National Institute for Health and Clinical Excellence. Ustekinumab for the treatment of adults with moderate to severe psoriasis. Technology appraisal TA180. London: NICE; September National Institute for Health and Clinical Excellence. Adalimumab for the treatment of adults with psoriasis. Technology appraisal TA146. London: NICE; June National Institute for Health and Clinical Excellence. Infliximab for the treatment of adults with psoriasis. Technology appraisal TA134. London: NICE; January National Institute for Health and Clinical Excellence. Etanercept and efalizumab for the treatment of adults with psoriasis. Technology appraisal TA103. London: NICE; July National Institute for Health and Clinical Excellence. Psoriasis: The assessment and management of psoriasis. Clinical guideline 153. London: NICE; October National Institute for Health and Clinical Excellence. Psoriasis. Quality standard in development. Expected Autumn National Institute for Health and Clinical Excellence. Grenz rays therapy for inflammatory skin conditions. Intervention procedure guidance IPG236. London: NICE; November Hsu S, Papp KA, Lebwohl MG et al. Consensus guidelines for the management of plaque psoriasis. Archives of Dermatolology. 2012;148: 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. July Accessed October British Association of Dermatologists & Primary Care Dermatology Society. Recommendations for the initial management of psoriasis. October PCDS%20Psoriasis%20reviewed% pdf Accessed 12 October Smith CH, Anstey AV, Barker JN et al. British Association of Dermatologists' guidelines for biologic interventions for psoriasis British Journal of Dermatology 2009;161(5): 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. September Accessed October 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. May Accessed October British Association of Dermatologists & Primary Care Dermatology Society. Recommendations for the initial management of psoriasis. October PCDS%20Psoriasis%20reviewed% pdf Accessed 6 December Map of Medicine (MoM), Psoriasis. International view. London: MoM; 2011 (Issue 4) Accessed 6 December British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 62. London: BMJ Group and RPS Publishing, September National Institute for Health and Clinical Excellence. Plaque psoriasis commissioning algorithm. London: NICE; January ClinicalTrials.gov. Phase 3b safety and efficacy study of apremilast to treat moderate to severe plaque-plaque psoriasis. Accessed 21 December

11 28 ClinicalTrials.gov. Study to evaluate safety and effectiveness of oral apremilast (CC-1004) in patients with moderate to severe plaque psoriasis (ESTEEM 1). Accessed 21 December ClinicalTrials.gov. Study to evaluate safety and effectiveness of oral apremilast (CC-10004) in patients with moderate to severe plaque psoriasis. (ESTEEM 2). w_locs=y Accessed 21 December Papp K, Cather JC, Rosoph L et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. The Lancet 2012;380(9843): ClinicalTrials.gov. Efficacy and safety study of apremilast (CC-10004) in subjects with moderatesevere plaque-type psoriasis (core study). nk=1 Accessed 21 December ClinicalTrials.gov. Extension study of apremilast to evaluate safety and efficacy in subjects with psoriasis who completed the treatment phase of the core study CC PSOR (PSOR-005E). w_locs=y Accessed 21 December Papp KA, Kaufmann R, Thaci D et al. Efficacy and safety of apremilast in subjects with moderate to sever plaque psoriasis: results from a phase II multicentre, randomized, double-blind placebocontrolled, parallel-group, dose-comparison study. Journal of the European Academy of Dermatology and Venereology. Doi: /j x 34 ClinicalTrials.gov. Double-blind, randomized, placebo-controlled comparison of CC in subjects with moderate to severe plaque type psoriasis (PSOR-003). Accessed 21 December ClinicalTrials.gov. Long-term safety extension of apremilast (CC-10004) in subjects who completed the treatment phase of extension study CC PSOR-005E (PSOR-005LTE). Accessed 7 January Gottlieb AB, Strober B, Krueger JG et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis reated with an oral anti-inflammatory agent, apremilast. Current Medical Research and Opinion 2008;24(5): ClinicalTrials.gov. Open-label, single-arm pilot study to evaluate the pharmacodynamics, pharmacokinetics, safety, and preliminary efficacy of CC1004 in subjects with severe plaque type psoriasis (PSOR-001). Accessed 7 January ClinicalTrials.gov. Phase 2, open-label study to evaluated apremilast recalcitrant (not responded to therapy) plaque-type psoriasis. Accessed 7 January British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September