- Email: [email protected]
Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naïve patients with psoriasis
ORIGINAL
ARTICLE
Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-na€ıve patients with psoriasis April W. Armstrong, MD, MPH,a Keith A. Betts, PhD,b Murali Sundaram, PhD,c Darren Thomason, BS,b and James E. Signorovitch, PhDb Los Angeles, California; Boston, Massachusetts; and Chicago, Illinois Background: To our knowledge, no clinical trials directly compare apremilast with methotrexate (the standard of care for initial systemic treatment of psoriasis). Objective: We sought to compare apremilast’s relative efficacy with that of methotrexate for moderate to severe psoriasis. Methods: An anchor-based indirect comparison was conducted for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) rates for systemic-na€ıve patients from Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis (ESTEEM) 1 and 2 (apremilast vs placebo) and Comparative study of HumirA vs. Methotrexate vs Placebo In psOriasis patieNts (CHAMPION) (adalimumab vs methotrexate vs placebo) trials. The difference-in-difference in PASI 75 response rates was calculated as the difference between the ESTEEM apremilast and placebo rates and the CHAMPION methotrexate versus placebo rates. Number needed to treat and incremental drug cost per responder were also estimated. Results: No statistically significant difference was found between apremilast and methotrexate in PASI 75 (risk difference 13.1%; 95% confidence interval 1.8% to 28.0%; P = .09). Number needed to treat with apremilast versus methotrexate to gain 1 additional PASI 75 responder was 7.6. Annual incremental drug cost of this responder was estimated at $187,888.33. Limitations: Few trials compare systemic-na€ıve patients. Only direct medication costs were considered. Conclusions: There was no statistical evidence of greater efficacy for apremilast versus methotrexate. The $187,888 incremental cost per PASI 75 may exceed what payers are willing to pay. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2016.05.040.) Key words: apremilast; cost per responder; cost-effectiveness; indirect comparison; methotrexate; moderate to severe psoriasis; number needed to treat; Psoriasis Area and Severity Index.
soriasis is a chronic, autoimmune disease that causes skin irritation, which can have an ongoing impact on patient well-being and
affects approximately 2% of the US population.1 Symptoms of psoriasis include itchy, painful erythematous plaques on the body’s surface and
From the Keck School of Medicine, University of Southern Californiaa; Analysis Group Inc, Bostonb; and AbbVie, North Chicago.c Funding for this study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript. Disclosure: Dr Armstrong serves as investigator and/or consultant to AbbVie, Amgen, Janssen, Merck, Lilly, Celgene, Novartis, Pfizer, and Modernizing Medicine. Drs Betts and Signorovitch and Mr Thomason are employed by Analysis Group Inc, which received payment from AbbVie for participation in this
research. Dr Sundaram is an employee of AbbVie and may own AbbVie stock or stock options. Presented in part at the Annual Meeting of the American Academy of Dermatology, San Francisco, CA, March 20-24, 2015. Accepted for publication May 17, 2016. Reprint requests: Keith A. Betts, PhD, Analysis Group Inc, 111 Huntington Ave, 14th Floor, Boston, MA 02199. E-mail: [email protected]. Published online July 28, 2016. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.05.040
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substantial impairment of health-related quality of not be derived because of a lack of relevant data life.2,3 In addition, the inflammatory process of psoagainst appropriate comparator therapy.23 To fill riasis is associated with numerous underlying cothese gaps, indirect comparisons of treatment outmorbidities, including cardiovascular disease and comes across separate randomized trials have diabetes. Simultaneously, it has been estimated that become a standard and valuable source of comparalmost 25% of patients with psoriasis have clinical ative evidence. Detailed methodological reviews and depression.4 In the past decade, psoriasis treatment implementation guidelines for indirect comparisons have been published, and has been revolutionized by indirect comparisons have highly efficacious biologic CAPSULE SUMMARY become a preferred evidence therapies.5,6 However, methsource for researchers and otrexate remains the most The relative effectiveness of apremilast medical decision makers.24commonly used treatment and methotrexate in treating psoriasis is 27 for psoriasis as it has been uncertain. the standard of care in the The purpose of this This study used indirect comparison clinical setting for over study is to formally evaluate methods to investigate the efficacy and 50 years.7,8 Methotrexate is the relative efficacy of aprecost of apremilast relative to milast and methotrexate recommended as one of the methotrexate. via indirect comparison to first-line therapies by both support informed first-line the American Academy of There was no statistical evidence of psoriasis treatment deciDermatology (AAD) and the greater efficacy for apremilast versus sions. In addition, because European Academy of methotrexate, although its cost was methotrexate is generically Dermatology and Venerosignificantly higher. available and less expenlogy.9,10 Apremilast, a smallsive, the relative costmolecule inhibitor of phoseffectiveness of apremilast and methotrexate will phodiesterase 4, was approved by the Food and provide important information for clinical and ecoDrug Administration (FDA) on September 24, 2014, nomic decision making. as a treatment for moderate to severe psoriasis. The clinical efficacy and safety of apremilast was METHODS evaluated in 2 large-scale, phase-III, randomized, A targeted literature review was conducted to placebo-controlled trials: ESTEEM 1 (NCT01194219) identify clinical trials that satisfied the following and ESTEEM 2 (NCT01232283).11,12 These trials inclusion criteria: (1) conducted among patients measured achievement of 75% improvement in with moderate to severe plaque psoriasis; (2) plaPsoriasis Area and Severity Index (PASI) score from cebo controlled; (3) reported PASI 75 response rates baseline to week 16 (PASI 75) as the primary end at week 16; (4) randomized patients to either point. Both trials found that rates of PASI 75 methotrexate or apremilast; and (5) reported results achievement among patients treated with apremilast stratified by experience with systemic therapy for (30 mg) were significantly higher than those of psoriasis. This literature leveraged previously conpatients treated with placebo. However, PASI 75 ducted systematic literature reviews.16,18,28 As the achievement rates (33.1% in ESTEEM 1 and 28.8% in majority of psoriasis trials are conducted among ESTEEM 2) were lower than those typically observed patients who were poorly controlled with systemic in biologic treatments for moderate to severe psoritherapy, ESTEEM 1, ESTEEM 2, and CHAMPION asis.13-18 In fact, the observed PASI 75 rates for were the only 3 trials that satisfied the inclusion apremilast were closer to those observed for methcriteria. otrexate (36.4% in the CHAMPION trial19) than to In the ESTEEM 1 (NCT01194219) and ESTEEM 2 etanercept at 50 mg twice weekly (observed range (NCT01232283) trials, patients were randomized to 47%-49%20-22). However, apremilast has not been apremilast (30 mg twice per day) or placebo. Patients directly compared with methotrexate in a head-toin the CHAMPION trial (NCT00235820) were ranhead randomized controlled trial. This lack of direct domized to receive adalimumab (40 mg every other comparative trials represents a substantial evidence week after a starter dose of 80 mg), methotrexate gap for health care decision makers, who need to (7.5 mg weekly increased as needed and as tolerated make treatment and reimbursement decisions. For to 25 mg), or placebo. All active medication doses example, the German Institute for Quality and administered were FDA approved. CHAMPION was Efficiency in Health Care (IQWiG) recently conducted among patients with moderate to severe concluded that the added benefit of apremilast could (body surface area $10%, and PASI score $10) d
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Abbreviations used: AAD: CI: FDA: ICPR: IQWiG:
American Academy of Dermatology confidence interval Food and Drug Administration incremental cost per responder German Institute for Quality and Efficiency in Health Care NNT: number needed to treat PASI: Psoriasis Area and Severity Index PASI 75: 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 RD: risk difference
psoriasis who were candidates for systemic therapy or phototherapy and who were na€ıve to both tumor necrosis factor-antagonist therapy and methotrexate. ESTEEM 1 and ESTEEM 2 were conducted among patients with moderate to severe (body surface area $10%, PASI score $10, and static Physician Global Assessment score $3) psoriasis for systemic therapy or phototherapy and patients previously treated with phototherapy/systemic therapy were permitted in the study. Both ESTEEM 1 and ESTEEM 2 reported results for a systemic-na€ıve subpopulation, making the data suitable for the indirect comparison between apremilast and methotrexate. Data for apremilast and placebo were extracted from presentations from the 71st and 72nd Annual Meeting of the AAD, published articles, and clinicaltrials.gov.11,12,29-32 The data from the ESTEEM trials were pooled as inclusion and exclusion criteria and relevant trial procedures were identical. Data for methotrexate and placebo were extracted from the 2008 primary publication of the CHAMPION trial by Saurat et al.19 Sixteen patients were lost to follow-up during the CHAMPION trial. To account for these discontinuations, the last observation carried forward population was used for the indirect comparison to be consistent with the published data from the ESTEEM trials. The outcome of interest for the indirect comparison was week 16 PASI 75 response rate. The PASI score is a measure of body surface area involvement and psoriasis severity.33 PASI 75 is the primary efficacy outcome in the majority of psoriasis trials. Additional relative efficacy measures (eg, 50% or 90% improvement in PASI score from baseline to week 16, static Physician Global Assessment score) were not considered for this study because of lack of reporting in the ESTEEM trials for the systemic-na€ıve population. A Bucher anchor-based indirect comparison was conducted to indirectly compare methotrexate and apremilast. The Bucher method is an adjusted
Fig 1. Diagram of the indirect comparison. MTX, Methotrexate.
indirect comparison that uses the magnitude of the effect measure reported in randomized controlled trials that separately compared 2 treatments (ie, methotrexate and apremilast) to a common comparator (ie, placebo) (Fig 1). The indirect comparison of methotrexate and apremilast can be estimated as a function of the direct comparisons of methotrexate versus placebo and of apremilast versus placebo. The Bucher method builds upon traditional direct meta-analysis and has been widely applied across therapeutic areas, and its statistical properties have been well-evaluated.24,34-37 The strengths of this approach are that it partially maintains the strength of randomization, and it can be applied with minimal information regarding the common indirect treatment comparison (ie, methotrexate vs placebo and apremilast vs placebo). The Bucher method was initially developed for the odds ratio effect measure, but extensions to other effect measures (eg, risk difference [RD], relative risk, hazard ratio) have been posited and validated.24,38 For this Bucher comparison, the difference in RD for both methotrexate versus apremilast, where the RD is the measure of the difference between the proportions of PASI 75 achievers within 2 populations, was calculated. RD was selected as the effect measure because it can be readily translated into number needed to treat (NNT). RD was separately calculated for the active arms versus the corresponding placebo arms within the CHAMPION and ESTEEM trials. The difference in RD was then calculated for apremilast versus methotrexate as shown in equation (1): Difference in RD ¼ fPASI 75MTX PASI 75PBO gCHAMPION ð1Þ fPASI 75APR PASI 75PBO gESTEEM where MTX is methotrexate, PBO is placebo, and APR is apremilast.
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Table I. Annual cost of active treatments Starter pack Active treatment
Maintenance therapy
Package Units Package Units cost* required cost* required
Apremilasty $843.75 Methotrexatez -
1 -
Table II. Achievers and response rates for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 Total cost
$2221.38 11.55 $26,501 $145.80 13.17 $1920
*Based on Wholesale Acquisition Costs. y Apremilast is dosed with a starter pack for the first 14 d and maintenance 30 mg twice/d thereafter. The maintenance pack has 60 30-mg pills. z Methotrexate is dosed at 7.5 mg for wk 0-1, 10 mg for wk 2-3, 15 mg for wk 4-6, 20 mg for wk 7-10, and 25 mg for wk 11-52.
The efficacy and cost for the indirect comparison were expressed in terms of NNT and incremental cost per responder (ICPR). The NNT, calculated as the reciprocal of the difference in RD, represents the number of patients needed to treat with the investigative drug (ie, apremilast) to achieve 1 additional PASI 75 responder as compared with the comparative drug (ie, methotrexate). A larger NNT indicates similar efficacy and a smaller NNT indicates a difference in efficacy. The meaningfulness of the NNT is extended by the ICPR, a measure of cost effectiveness. The ICPR estimates the cost of each additional responder conveyed by the NNT and is calculated by multiplying the total annual drug costs by the NNT. The drug costs are based on 2015 dollars, obtained from Red Book Online,39 and detailed in Table I.39
RESULTS A total of 645 methotrexate-na€ıve patients were available from the ESTEEM 1 and ESTEEM 2 trials, and 163 patients were available from the CHAMPION trial for this analysis. There were 429 patients randomized to apremilast and 216 randomized to placebo in the ESTEEM trials; and 110 randomized to methotrexate and 53 randomized to placebo in the CHAMPION trial. Of the patients in the study, 36.6% of patients taking apremilast and 36.4% of patients taking methotrexate achieved PASI 75 after 16 weeks. Placebo response rates were 18.9% in CHAMPION and 6.0% in the pooled ESTEEM trials. The numbers of patients who achieved PASI 75 in each treatment arm are shown in Table II. The RD between the active arms was differenced from the RD between the placebo arms to give the indirect comparison between each therapy. The RD between apremilast and methotrexate was 0.2% and the RD between the corresponding placebo arms was 12.8%, making the difference in RD 13.1% (95% confidence interval [CI] 1.8% to 28.0%; P value .086).
Trial
Treatment arm
ESTEEM Apremilast 1 and 2* Placebo CHAMPION Methotrexate Placebo
Wk 16 SystemicPASI 75 PASI 75 na€ıve response achievers sample size rate
157 13 40 10
429 216 110 53
36.6% 6.0% 36.4% 18.9%
PASI 75, 75% Improvement in Psoriasis Area and Severity Index score from baseline to week 16. *Based on pooled ESTEEM 1 and ESTEEM 2 trial results.
The NNT between apremilast and methotrexate was estimated at 7.644 (95% CI (N, 54.42) W (3.57, N)), implying that it would take nearly 8 patients to be treated with apremilast instead of methotrexate to gain 1 additional PASI 75 responder (Fig 2). It should be noted that because the difference in RD between apremilast and methotrexate was not statistically significant, the 95% CI for the NNT between apremilast and methotrexate is a union of sets ranging from an NNT of 3.57 to a number needed to harm of 54.42.40 The NNT calculated based on the differences in RD was applied to the annual drug costs to estimate the ICPR, a measure of the incremental cost of each additional responder identified by the NNT. The ICPR of apremilast versus methotrexate was estimated at $187,888.33 (95% CI (N, $1,337,639.65) W ($87,779.31, N)), meaning that each additional PASI 75 responder gained by patients using apremilast instead of methotrexate would come at a cost of more than $150,000 (Fig 3).
DISCUSSION Reliable evidence about the comparative efficacy and cost-effectiveness of apremilast is needed to inform clinical and economic decisions about its use in the treatment of moderate to severe psoriasis. The efficacy of apremilast relative to placebo was established in 2 randomized controlled trials. However, there remains an evidence gap regarding the comparative efficacy and cost-effectiveness of apremilast relative to alternative treatments for moderate to severe psoriasis. Over time, observational studies based on registries or real-world data may help to close this gap. However, in the absence of head-to-head clinical trials and real-world evidence, well-conducted indirect comparisons based on rigorous and transparent methodology represent the best evidence available to make critical treatment and reimbursement decisions.
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Fig 2. Numbers needed to treat (NNT) to achieve 1 additional 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) responder. Black bars, 95% Confidence intervals for the NNT. Arrow, 95% Confidence extends to infinity and includes a region where methotrexate (MTX ) is more effective than apremilast (APR).
This study used data from published trials of systemic-na€ıve patients with moderate to severe psoriasis to compare the PASI 75 response rates, NNT, and ICPR for apremilast versus methotrexate. The indirect comparison was conducted using rigorous statistical methodology that has been accepted by the US Agency for Healthcare Research and Quality,41 United Kingdom National Health Service Health Technology Assessment Program,42 IQWiG,43 Canadian Agency for Drugs and Technologies in Health,24 and the Australian Pharmaceutical Benefits Advisory Committee.44 In terms of PASI 75 response rate, this study found no statistically significant differences between apremilast and methotrexate. However, the additional cost of apremilast rather than methotrexate was estimated at approximately $188,000 per year for each additional PASI 75 responder. These results are similar to a separate indirect comparison conducted in active psoriatic arthritis.45 These results are also consistent with a separate study that found methotrexate had lower costs per responder than phototherapy, acitretin, cyclosporine, and biologic therapies for the treatment of psoriasis.46 It should be noted that ESTEEM trials and the CHAMPION trial have different placebo response rates (7.6% for ESTEEM 1, 3.6% for ESTEEM 2, and 18.9% for CHAMPION), which may be an indication that the similarity assumption (ie, that the distribution of effect modifiers is balanced across trials) is violated. However, the difference in RD takes these differences in placebo response rate into account, and in fact, they drive the overall difference observed (the total difference in RD was 13.1%, of which the difference in placebo response accounts for 12.8 percentage points, or roughly 98%). Therefore, this difference-in-difference may overestimate the efficacy difference between apremilast and methotrexate. However, even with this potential
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Fig 3. Incremental costs per 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) responder over 1 year. Black bars, 95% Confidence intervals for the incremental costs per responder. Arrow, 95% Confidence extends to infinity and includes a region where methotrexate (MTX ) is more effective than apremilast (APR).
overestimation, the ICPR is high, owing almost entirely to difference in cost between apremilast and methotrexate. In fact at the current prices, the difference in PASI 75 response rates would need to be 41.2% for the ICPR to fall below $50,000. Alternatively, the annual price of apremilast would need to be reduced by $18,039 (from $26,501 to $8461) to meet the same $50,000 threshold. Two potential limitations of this study are the limited number of trials available to compare systemic-na€ıve patients and the lack of accounting for adverse events. Although methotrexate has been a staple of psoriasis treatment for 50 years, the number of clinical trials of methotrexate is limited. Two trials compared methotrexate with cyclosporine,47,48 1 trial compared methotrexate with fumarates,49 1 trial compared methotrexate with infliximab,50 and 1 trial compared 2 fixed dosages of methotrexate.51 These trials could not be included in the meta-analysis because of their lack of a common comparator arm (ie, placebo). Even the CHAMPION trial that compared methotrexate and placebo was limited by a relatively small sample size. In addition, this analysis only considers direct medication costs, and does not include costs related to adverse events or methotrexate hepatotoxicity. Although the inclusion of such costs may reduce the ICPR, the magnitude of the reduction is unlikely to change the overall conclusion.52 For example, a previous study estimated that the total monitoring and toxicity costs associated with methotrexate were $1062 over 6 months in a methotrexate-na€ıve population.53,54 Including these costs (inflated to 2015 dollars), this calculation still would yield an ICPR of apremilast versus methotrexate of roughly $160,000.
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In summary, among systemic-na€ıve patients with moderate to severe psoriasis, there were no statistically significant differences between apremilast and methotrexate. In addition, the ICPR with apremilast versus methotrexate is high. As this study provides the only relevant data to our knowledge for apremilast against an appropriate comparator therapy, these results could provide clinically and economically relevant implications for health care decision makers. REFERENCES 1. Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160:810-820. 2. Gottlieb AB, Chao C, Dann F. Psoriasis comorbidities. J Dermatolog Treat. 2008;19:5-21. 3. Kimball AB, Jacobson C, Weiss S, et al. The psychosocial burden of psoriasis. Am J Clin Dermatol. 2005;6:383-392. 4. Gupta MA, Gupta AK. Psoriasis and sex: a study of moderately to severely affected patients. Int J Dermatol. 1997;36:259-262. 5. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res. 2006;298:7-15. 6. Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012; 148:95-102. 7. Edmundson WF, Guy WB. Treatment of psoriasis with folic acid antagonists. AMA Arch Derm. 1958;78:200-203. 8. Smith KC. Systemic therapy of psoriasis using methotrexate. Skin Therapy Lett. 2000;6:1-2. 9. Menter A, Korman NJ, Elmets CA, et al, American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2008;60:643-659. 10. Pathirana D, Ormerod AD, Saiag P, et al. European S3guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009;23:1-70. 11. Reich K, Papp K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 1). Poster session presented at: 71st Annual Meeting of the American Academy of Dermatology; March 1-5, 2014; Miami, FL. 12. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). Poster session presented at: 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2015; Denver, CO. 13. Woolacott N, Hawkins N, Mason A, et al. Etanercept and efalizumab for the treatment of psoriasis: a systematic review. Health Technol Assess. 2006;10:1-233. 14. Bansback N, Sizto S, Sun H, et al. Efficacy of systemic treatments for moderate to severe plaque psoriasis: systematic review and meta-analysis. Dermatology. 2009; 219:209-218. 15. Reich K, Burden AD, Eaton JN, et al. Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials. Br J Dermatol. 2012;166:179-188. 16. Lin VW, Ringold S, Devine EB. Comparison of ustekinumab with other biological agents for the treatment of moderate
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moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73:37-49. Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015;173:1387-1399. Fredriksson T, Pettersson U. Severe psoriasis e oral therapy with a new retinoid. Dermatologica. 1978;157:238-244. Vandermeer BW, Buscemi N, Liang Y, Witmans M. Comparison of meta-analytic results of indirect, direct, and combined comparisons of drugs for chronic insomnia in adults: a case study. Med Care. 2007;45(10 Suppl 2): S166-S172. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6): 683-691. Song F, Loke YK, Walsh T, et al. Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. Bmj. 2009;338:b1147. Song F, Clark A, Bachmann MO, Maas J. Simulation evaluation of statistical properties of methods for indirect and mixed treatment comparisons. BMC Med Res Methodol. 2012;12(1): 138. Coomarasamy A, Knox EM, Gee H, et al. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labor: a meta-analysis with an indirect comparison of randomized trials. BJOG. 2003;110(12):1045-1049. Truven Health Analytics Inc. Unit costs for all treatments are based on Red Book Online. Available from: URL: http://www. redbook.com/redbook/. Accessed August 5, 2015. Altman DG. Confidence intervals for the number needed to treat. BMJ. 1998;317(7168):1309. Agency for Healthcare Research and Quality. Methods reference guide for effectiveness and comparative effectiveness reviews. Version 1.0. Available from: URL: www.effectivehealthcare.ahrq. gov/repFiles/2007_10DraftMethodsGuide.pdf. Accessed June 12, 2015. 2008 National Institute for Health and Clinical Excellence (NICE). Guide to the methods of technology appraisal. Available from: URL: www.nice.org.uk/media/B52/A7/TAMethodsGuideUpdate dJune2008.pdf. Accessed June 12, 2015. Bekkering GE, Kleijnen J. Procedures and methods of benefit assessments for medicines in Germany. Eur J Health Econ. 2008;9:5-29.
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44. Indirect Comparison Working Group (ICWG). Report of the Indirect Comparisons Working Group to the Pharmaceutical Benefits Advisory Committee: assessing indirect comparisons. Available from: URL: www.health.gov.au/internet/main/ publishing.nsf/Content/B11E8EF19B358E39CA25754B000A9 C07/$File/ICWG %20Report%20FINAL2.pdf. Accessed June 12, 2015. 45. Betts KA, Griffith J, Friedman A, Zhou ZY, Signorovitch JE, Ganguli A. An indirect comparison and cost per responder analysis of adalimumab, methotrexate and apremilast in the treatment of methotrexate-na€ıve patients with psoriatic arthritis. Curr Med Res Opin. 2016;32(4):721-729. 46. D’Souza LS, Payette MJ. Estimated cost efficacy of systemic treatments that are approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis. J Am Acad Dermatol. 2015;72(4):589-598. 47. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349:658-665. 48. Flytstrom I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs cyclosporin in psoriasis: effectiveness, quality of life and safety: a randomized controlled trial. Br J Dermatol. 2008; 158:116-121. 49. Fallah Arani S, Neumann H, Hop WC, Thio HB. Fumarates vs methotrexate in moderate to severe chronic plaque psoriasis: a multicenter prospective randomized controlled clinical trial. Br J Dermatol. 2011;164:855-861. 50. Barker J, Hoffmann M, Wozel G, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1). Br J Dermatol. 2011;165:1109-1117. 51. Dogra S, Krishna V, Kanwar AJ. Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study. Clin Exp Dermatol. 2012;37:729-734. 52. Barker J, Horn EJ, Lebwohl M, et al. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J Eur Acad Dermatol Venereol. 2011;25:758-764. 53. Prashker MJ, Meenan RF. The total costs of drug therapy for rheumatoid arthritis: a model based on costs of drug, monitoring, and toxicity. Arthritis Rheum. 1995;38:318-325. 54. Choi HK, Seeger JD, Kuntz KM. A cost effectiveness analysis of treatment options for methotrexate-na€ıve rheumatoid arthritis. J Rheumatol. 2002;29:1156-1165.
ARTICLE
Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-na€ıve patients with psoriasis April W. Armstrong, MD, MPH,a Keith A. Betts, PhD,b Murali Sundaram, PhD,c Darren Thomason, BS,b and James E. Signorovitch, PhDb Los Angeles, California; Boston, Massachusetts; and Chicago, Illinois Background: To our knowledge, no clinical trials directly compare apremilast with methotrexate (the standard of care for initial systemic treatment of psoriasis). Objective: We sought to compare apremilast’s relative efficacy with that of methotrexate for moderate to severe psoriasis. Methods: An anchor-based indirect comparison was conducted for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) rates for systemic-na€ıve patients from Efficacy and Safety Trial Evaluating the Effects of apreMilast in psoriasis (ESTEEM) 1 and 2 (apremilast vs placebo) and Comparative study of HumirA vs. Methotrexate vs Placebo In psOriasis patieNts (CHAMPION) (adalimumab vs methotrexate vs placebo) trials. The difference-in-difference in PASI 75 response rates was calculated as the difference between the ESTEEM apremilast and placebo rates and the CHAMPION methotrexate versus placebo rates. Number needed to treat and incremental drug cost per responder were also estimated. Results: No statistically significant difference was found between apremilast and methotrexate in PASI 75 (risk difference 13.1%; 95% confidence interval 1.8% to 28.0%; P = .09). Number needed to treat with apremilast versus methotrexate to gain 1 additional PASI 75 responder was 7.6. Annual incremental drug cost of this responder was estimated at $187,888.33. Limitations: Few trials compare systemic-na€ıve patients. Only direct medication costs were considered. Conclusions: There was no statistical evidence of greater efficacy for apremilast versus methotrexate. The $187,888 incremental cost per PASI 75 may exceed what payers are willing to pay. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2016.05.040.) Key words: apremilast; cost per responder; cost-effectiveness; indirect comparison; methotrexate; moderate to severe psoriasis; number needed to treat; Psoriasis Area and Severity Index.
soriasis is a chronic, autoimmune disease that causes skin irritation, which can have an ongoing impact on patient well-being and
affects approximately 2% of the US population.1 Symptoms of psoriasis include itchy, painful erythematous plaques on the body’s surface and
From the Keck School of Medicine, University of Southern Californiaa; Analysis Group Inc, Bostonb; and AbbVie, North Chicago.c Funding for this study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript. Disclosure: Dr Armstrong serves as investigator and/or consultant to AbbVie, Amgen, Janssen, Merck, Lilly, Celgene, Novartis, Pfizer, and Modernizing Medicine. Drs Betts and Signorovitch and Mr Thomason are employed by Analysis Group Inc, which received payment from AbbVie for participation in this
research. Dr Sundaram is an employee of AbbVie and may own AbbVie stock or stock options. Presented in part at the Annual Meeting of the American Academy of Dermatology, San Francisco, CA, March 20-24, 2015. Accepted for publication May 17, 2016. Reprint requests: Keith A. Betts, PhD, Analysis Group Inc, 111 Huntington Ave, 14th Floor, Boston, MA 02199. E-mail: [email protected]. Published online July 28, 2016. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.05.040
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substantial impairment of health-related quality of not be derived because of a lack of relevant data life.2,3 In addition, the inflammatory process of psoagainst appropriate comparator therapy.23 To fill riasis is associated with numerous underlying cothese gaps, indirect comparisons of treatment outmorbidities, including cardiovascular disease and comes across separate randomized trials have diabetes. Simultaneously, it has been estimated that become a standard and valuable source of comparalmost 25% of patients with psoriasis have clinical ative evidence. Detailed methodological reviews and depression.4 In the past decade, psoriasis treatment implementation guidelines for indirect comparisons have been published, and has been revolutionized by indirect comparisons have highly efficacious biologic CAPSULE SUMMARY become a preferred evidence therapies.5,6 However, methsource for researchers and otrexate remains the most The relative effectiveness of apremilast medical decision makers.24commonly used treatment and methotrexate in treating psoriasis is 27 for psoriasis as it has been uncertain. the standard of care in the The purpose of this This study used indirect comparison clinical setting for over study is to formally evaluate methods to investigate the efficacy and 50 years.7,8 Methotrexate is the relative efficacy of aprecost of apremilast relative to milast and methotrexate recommended as one of the methotrexate. via indirect comparison to first-line therapies by both support informed first-line the American Academy of There was no statistical evidence of psoriasis treatment deciDermatology (AAD) and the greater efficacy for apremilast versus sions. In addition, because European Academy of methotrexate, although its cost was methotrexate is generically Dermatology and Venerosignificantly higher. available and less expenlogy.9,10 Apremilast, a smallsive, the relative costmolecule inhibitor of phoseffectiveness of apremilast and methotrexate will phodiesterase 4, was approved by the Food and provide important information for clinical and ecoDrug Administration (FDA) on September 24, 2014, nomic decision making. as a treatment for moderate to severe psoriasis. The clinical efficacy and safety of apremilast was METHODS evaluated in 2 large-scale, phase-III, randomized, A targeted literature review was conducted to placebo-controlled trials: ESTEEM 1 (NCT01194219) identify clinical trials that satisfied the following and ESTEEM 2 (NCT01232283).11,12 These trials inclusion criteria: (1) conducted among patients measured achievement of 75% improvement in with moderate to severe plaque psoriasis; (2) plaPsoriasis Area and Severity Index (PASI) score from cebo controlled; (3) reported PASI 75 response rates baseline to week 16 (PASI 75) as the primary end at week 16; (4) randomized patients to either point. Both trials found that rates of PASI 75 methotrexate or apremilast; and (5) reported results achievement among patients treated with apremilast stratified by experience with systemic therapy for (30 mg) were significantly higher than those of psoriasis. This literature leveraged previously conpatients treated with placebo. However, PASI 75 ducted systematic literature reviews.16,18,28 As the achievement rates (33.1% in ESTEEM 1 and 28.8% in majority of psoriasis trials are conducted among ESTEEM 2) were lower than those typically observed patients who were poorly controlled with systemic in biologic treatments for moderate to severe psoritherapy, ESTEEM 1, ESTEEM 2, and CHAMPION asis.13-18 In fact, the observed PASI 75 rates for were the only 3 trials that satisfied the inclusion apremilast were closer to those observed for methcriteria. otrexate (36.4% in the CHAMPION trial19) than to In the ESTEEM 1 (NCT01194219) and ESTEEM 2 etanercept at 50 mg twice weekly (observed range (NCT01232283) trials, patients were randomized to 47%-49%20-22). However, apremilast has not been apremilast (30 mg twice per day) or placebo. Patients directly compared with methotrexate in a head-toin the CHAMPION trial (NCT00235820) were ranhead randomized controlled trial. This lack of direct domized to receive adalimumab (40 mg every other comparative trials represents a substantial evidence week after a starter dose of 80 mg), methotrexate gap for health care decision makers, who need to (7.5 mg weekly increased as needed and as tolerated make treatment and reimbursement decisions. For to 25 mg), or placebo. All active medication doses example, the German Institute for Quality and administered were FDA approved. CHAMPION was Efficiency in Health Care (IQWiG) recently conducted among patients with moderate to severe concluded that the added benefit of apremilast could (body surface area $10%, and PASI score $10) d
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Abbreviations used: AAD: CI: FDA: ICPR: IQWiG:
American Academy of Dermatology confidence interval Food and Drug Administration incremental cost per responder German Institute for Quality and Efficiency in Health Care NNT: number needed to treat PASI: Psoriasis Area and Severity Index PASI 75: 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 RD: risk difference
psoriasis who were candidates for systemic therapy or phototherapy and who were na€ıve to both tumor necrosis factor-antagonist therapy and methotrexate. ESTEEM 1 and ESTEEM 2 were conducted among patients with moderate to severe (body surface area $10%, PASI score $10, and static Physician Global Assessment score $3) psoriasis for systemic therapy or phototherapy and patients previously treated with phototherapy/systemic therapy were permitted in the study. Both ESTEEM 1 and ESTEEM 2 reported results for a systemic-na€ıve subpopulation, making the data suitable for the indirect comparison between apremilast and methotrexate. Data for apremilast and placebo were extracted from presentations from the 71st and 72nd Annual Meeting of the AAD, published articles, and clinicaltrials.gov.11,12,29-32 The data from the ESTEEM trials were pooled as inclusion and exclusion criteria and relevant trial procedures were identical. Data for methotrexate and placebo were extracted from the 2008 primary publication of the CHAMPION trial by Saurat et al.19 Sixteen patients were lost to follow-up during the CHAMPION trial. To account for these discontinuations, the last observation carried forward population was used for the indirect comparison to be consistent with the published data from the ESTEEM trials. The outcome of interest for the indirect comparison was week 16 PASI 75 response rate. The PASI score is a measure of body surface area involvement and psoriasis severity.33 PASI 75 is the primary efficacy outcome in the majority of psoriasis trials. Additional relative efficacy measures (eg, 50% or 90% improvement in PASI score from baseline to week 16, static Physician Global Assessment score) were not considered for this study because of lack of reporting in the ESTEEM trials for the systemic-na€ıve population. A Bucher anchor-based indirect comparison was conducted to indirectly compare methotrexate and apremilast. The Bucher method is an adjusted
Fig 1. Diagram of the indirect comparison. MTX, Methotrexate.
indirect comparison that uses the magnitude of the effect measure reported in randomized controlled trials that separately compared 2 treatments (ie, methotrexate and apremilast) to a common comparator (ie, placebo) (Fig 1). The indirect comparison of methotrexate and apremilast can be estimated as a function of the direct comparisons of methotrexate versus placebo and of apremilast versus placebo. The Bucher method builds upon traditional direct meta-analysis and has been widely applied across therapeutic areas, and its statistical properties have been well-evaluated.24,34-37 The strengths of this approach are that it partially maintains the strength of randomization, and it can be applied with minimal information regarding the common indirect treatment comparison (ie, methotrexate vs placebo and apremilast vs placebo). The Bucher method was initially developed for the odds ratio effect measure, but extensions to other effect measures (eg, risk difference [RD], relative risk, hazard ratio) have been posited and validated.24,38 For this Bucher comparison, the difference in RD for both methotrexate versus apremilast, where the RD is the measure of the difference between the proportions of PASI 75 achievers within 2 populations, was calculated. RD was selected as the effect measure because it can be readily translated into number needed to treat (NNT). RD was separately calculated for the active arms versus the corresponding placebo arms within the CHAMPION and ESTEEM trials. The difference in RD was then calculated for apremilast versus methotrexate as shown in equation (1): Difference in RD ¼ fPASI 75MTX PASI 75PBO gCHAMPION ð1Þ fPASI 75APR PASI 75PBO gESTEEM where MTX is methotrexate, PBO is placebo, and APR is apremilast.
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Table I. Annual cost of active treatments Starter pack Active treatment
Maintenance therapy
Package Units Package Units cost* required cost* required
Apremilasty $843.75 Methotrexatez -
1 -
Table II. Achievers and response rates for 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 Total cost
$2221.38 11.55 $26,501 $145.80 13.17 $1920
*Based on Wholesale Acquisition Costs. y Apremilast is dosed with a starter pack for the first 14 d and maintenance 30 mg twice/d thereafter. The maintenance pack has 60 30-mg pills. z Methotrexate is dosed at 7.5 mg for wk 0-1, 10 mg for wk 2-3, 15 mg for wk 4-6, 20 mg for wk 7-10, and 25 mg for wk 11-52.
The efficacy and cost for the indirect comparison were expressed in terms of NNT and incremental cost per responder (ICPR). The NNT, calculated as the reciprocal of the difference in RD, represents the number of patients needed to treat with the investigative drug (ie, apremilast) to achieve 1 additional PASI 75 responder as compared with the comparative drug (ie, methotrexate). A larger NNT indicates similar efficacy and a smaller NNT indicates a difference in efficacy. The meaningfulness of the NNT is extended by the ICPR, a measure of cost effectiveness. The ICPR estimates the cost of each additional responder conveyed by the NNT and is calculated by multiplying the total annual drug costs by the NNT. The drug costs are based on 2015 dollars, obtained from Red Book Online,39 and detailed in Table I.39
RESULTS A total of 645 methotrexate-na€ıve patients were available from the ESTEEM 1 and ESTEEM 2 trials, and 163 patients were available from the CHAMPION trial for this analysis. There were 429 patients randomized to apremilast and 216 randomized to placebo in the ESTEEM trials; and 110 randomized to methotrexate and 53 randomized to placebo in the CHAMPION trial. Of the patients in the study, 36.6% of patients taking apremilast and 36.4% of patients taking methotrexate achieved PASI 75 after 16 weeks. Placebo response rates were 18.9% in CHAMPION and 6.0% in the pooled ESTEEM trials. The numbers of patients who achieved PASI 75 in each treatment arm are shown in Table II. The RD between the active arms was differenced from the RD between the placebo arms to give the indirect comparison between each therapy. The RD between apremilast and methotrexate was 0.2% and the RD between the corresponding placebo arms was 12.8%, making the difference in RD 13.1% (95% confidence interval [CI] 1.8% to 28.0%; P value .086).
Trial
Treatment arm
ESTEEM Apremilast 1 and 2* Placebo CHAMPION Methotrexate Placebo
Wk 16 SystemicPASI 75 PASI 75 na€ıve response achievers sample size rate
157 13 40 10
429 216 110 53
36.6% 6.0% 36.4% 18.9%
PASI 75, 75% Improvement in Psoriasis Area and Severity Index score from baseline to week 16. *Based on pooled ESTEEM 1 and ESTEEM 2 trial results.
The NNT between apremilast and methotrexate was estimated at 7.644 (95% CI (N, 54.42) W (3.57, N)), implying that it would take nearly 8 patients to be treated with apremilast instead of methotrexate to gain 1 additional PASI 75 responder (Fig 2). It should be noted that because the difference in RD between apremilast and methotrexate was not statistically significant, the 95% CI for the NNT between apremilast and methotrexate is a union of sets ranging from an NNT of 3.57 to a number needed to harm of 54.42.40 The NNT calculated based on the differences in RD was applied to the annual drug costs to estimate the ICPR, a measure of the incremental cost of each additional responder identified by the NNT. The ICPR of apremilast versus methotrexate was estimated at $187,888.33 (95% CI (N, $1,337,639.65) W ($87,779.31, N)), meaning that each additional PASI 75 responder gained by patients using apremilast instead of methotrexate would come at a cost of more than $150,000 (Fig 3).
DISCUSSION Reliable evidence about the comparative efficacy and cost-effectiveness of apremilast is needed to inform clinical and economic decisions about its use in the treatment of moderate to severe psoriasis. The efficacy of apremilast relative to placebo was established in 2 randomized controlled trials. However, there remains an evidence gap regarding the comparative efficacy and cost-effectiveness of apremilast relative to alternative treatments for moderate to severe psoriasis. Over time, observational studies based on registries or real-world data may help to close this gap. However, in the absence of head-to-head clinical trials and real-world evidence, well-conducted indirect comparisons based on rigorous and transparent methodology represent the best evidence available to make critical treatment and reimbursement decisions.
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Fig 2. Numbers needed to treat (NNT) to achieve 1 additional 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) responder. Black bars, 95% Confidence intervals for the NNT. Arrow, 95% Confidence extends to infinity and includes a region where methotrexate (MTX ) is more effective than apremilast (APR).
This study used data from published trials of systemic-na€ıve patients with moderate to severe psoriasis to compare the PASI 75 response rates, NNT, and ICPR for apremilast versus methotrexate. The indirect comparison was conducted using rigorous statistical methodology that has been accepted by the US Agency for Healthcare Research and Quality,41 United Kingdom National Health Service Health Technology Assessment Program,42 IQWiG,43 Canadian Agency for Drugs and Technologies in Health,24 and the Australian Pharmaceutical Benefits Advisory Committee.44 In terms of PASI 75 response rate, this study found no statistically significant differences between apremilast and methotrexate. However, the additional cost of apremilast rather than methotrexate was estimated at approximately $188,000 per year for each additional PASI 75 responder. These results are similar to a separate indirect comparison conducted in active psoriatic arthritis.45 These results are also consistent with a separate study that found methotrexate had lower costs per responder than phototherapy, acitretin, cyclosporine, and biologic therapies for the treatment of psoriasis.46 It should be noted that ESTEEM trials and the CHAMPION trial have different placebo response rates (7.6% for ESTEEM 1, 3.6% for ESTEEM 2, and 18.9% for CHAMPION), which may be an indication that the similarity assumption (ie, that the distribution of effect modifiers is balanced across trials) is violated. However, the difference in RD takes these differences in placebo response rate into account, and in fact, they drive the overall difference observed (the total difference in RD was 13.1%, of which the difference in placebo response accounts for 12.8 percentage points, or roughly 98%). Therefore, this difference-in-difference may overestimate the efficacy difference between apremilast and methotrexate. However, even with this potential
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Fig 3. Incremental costs per 75% improvement in Psoriasis Area and Severity Index score from baseline to week 16 (PASI 75) responder over 1 year. Black bars, 95% Confidence intervals for the incremental costs per responder. Arrow, 95% Confidence extends to infinity and includes a region where methotrexate (MTX ) is more effective than apremilast (APR).
overestimation, the ICPR is high, owing almost entirely to difference in cost between apremilast and methotrexate. In fact at the current prices, the difference in PASI 75 response rates would need to be 41.2% for the ICPR to fall below $50,000. Alternatively, the annual price of apremilast would need to be reduced by $18,039 (from $26,501 to $8461) to meet the same $50,000 threshold. Two potential limitations of this study are the limited number of trials available to compare systemic-na€ıve patients and the lack of accounting for adverse events. Although methotrexate has been a staple of psoriasis treatment for 50 years, the number of clinical trials of methotrexate is limited. Two trials compared methotrexate with cyclosporine,47,48 1 trial compared methotrexate with fumarates,49 1 trial compared methotrexate with infliximab,50 and 1 trial compared 2 fixed dosages of methotrexate.51 These trials could not be included in the meta-analysis because of their lack of a common comparator arm (ie, placebo). Even the CHAMPION trial that compared methotrexate and placebo was limited by a relatively small sample size. In addition, this analysis only considers direct medication costs, and does not include costs related to adverse events or methotrexate hepatotoxicity. Although the inclusion of such costs may reduce the ICPR, the magnitude of the reduction is unlikely to change the overall conclusion.52 For example, a previous study estimated that the total monitoring and toxicity costs associated with methotrexate were $1062 over 6 months in a methotrexate-na€ıve population.53,54 Including these costs (inflated to 2015 dollars), this calculation still would yield an ICPR of apremilast versus methotrexate of roughly $160,000.
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In summary, among systemic-na€ıve patients with moderate to severe psoriasis, there were no statistically significant differences between apremilast and methotrexate. In addition, the ICPR with apremilast versus methotrexate is high. As this study provides the only relevant data to our knowledge for apremilast against an appropriate comparator therapy, these results could provide clinically and economically relevant implications for health care decision makers. REFERENCES 1. Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160:810-820. 2. Gottlieb AB, Chao C, Dann F. Psoriasis comorbidities. J Dermatolog Treat. 2008;19:5-21. 3. Kimball AB, Jacobson C, Weiss S, et al. The psychosocial burden of psoriasis. Am J Clin Dermatol. 2005;6:383-392. 4. Gupta MA, Gupta AK. Psoriasis and sex: a study of moderately to severely affected patients. Int J Dermatol. 1997;36:259-262. 5. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res. 2006;298:7-15. 6. Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012; 148:95-102. 7. Edmundson WF, Guy WB. Treatment of psoriasis with folic acid antagonists. AMA Arch Derm. 1958;78:200-203. 8. Smith KC. Systemic therapy of psoriasis using methotrexate. Skin Therapy Lett. 2000;6:1-2. 9. Menter A, Korman NJ, Elmets CA, et al, American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol. 2008;60:643-659. 10. Pathirana D, Ormerod AD, Saiag P, et al. European S3guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2009;23:1-70. 11. Reich K, Papp K, Leonardi C, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 1). Poster session presented at: 71st Annual Meeting of the American Academy of Dermatology; March 1-5, 2014; Miami, FL. 12. Paul C, Cather J, Gooderham M, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe psoriasis: 16-week results of a phase 3, randomized, controlled trial (ESTEEM 2). Poster session presented at: 72nd Annual Meeting of the American Academy of Dermatology; March 21-25, 2015; Denver, CO. 13. Woolacott N, Hawkins N, Mason A, et al. Etanercept and efalizumab for the treatment of psoriasis: a systematic review. Health Technol Assess. 2006;10:1-233. 14. Bansback N, Sizto S, Sun H, et al. Efficacy of systemic treatments for moderate to severe plaque psoriasis: systematic review and meta-analysis. Dermatology. 2009; 219:209-218. 15. Reich K, Burden AD, Eaton JN, et al. Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials. Br J Dermatol. 2012;166:179-188. 16. Lin VW, Ringold S, Devine EB. Comparison of ustekinumab with other biological agents for the treatment of moderate
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