Eur J Dermatol 2014; 24(5): 523-32

Review article Knud KRAGBALLE1 Peter C.M. VAN DE KERKHOF2 Kenneth B. GORDON3 1

Dept of Dermatology, Århus University Hospital, Århus Sygehus, P.P. Ørums Gade 11, 8000 Århus, Denmark 2 Dept of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Dept of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA

Reprints: K. Kragballe

Article accepted on 5/09/2014

Unmet needs in the treatment of psoriasis Biologics have greatly improved the treatment of moderate-to-severe plaque psoriasis, as most patients are now able to achieve an initial improvement of 75% in the Psoriasis Area and Severity Index. However, only ∼20%-57% reach a 90% improvement in this measurement and responses may be lost over time. In addition, there are potential safety issues as TNF-inhibitor biologics have been associated with infections or non-melanoma skin malignancies. Here we review unmet needs with current therapies for psoriasis. We researched the medical literature to discuss new therapies in development and assess their potential to meet these needs. Several new classes of anti-psoriatic drugs are currently undergoing clinical development and potential improvements with these new therapies include attaining earlier and higher-level responses that are durable, more specific targeting of cytokines involved directly in psoriatic inflammation, and new therapies offering convenient administration. Additionally, based on results from clinical trials evaluating these new agents, it may be possible to find predictive markers that identify patients best treated with certain drug classes, those prone to lose treatment responses and patients who can discontinue treatment and remain in remission. It remains to be determined whether the promising results seen in early studies of therapies in development for psoriasis will translate into actual improvements over currently available treatment options. Key words: biologics, interleukin-17 blockers, interleukin-23 blockers, psoriasis, Psoriasis Area and Severity Index, secukinumab

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doi:10.1684/ejd.2014.2403

soriasis is a chronic, immune-mediated disease affecting approximately 2%-3% of the population worldwide [1, 2]. Plaque psoriasis is the most common type, accounting for >80% of cases [3]. Assessing disease severity is a complex process as it involves the extent of skin involvement, disease location and impact on healthrelated quality of life. Treatment aims at complete clearance of all skin symptoms, but in clinical practice achieving and maintaining a 75% decrease in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 75) has been a more realistic and practical goal for patients with moderateto-severe disease [4]. The introduction of biologic therapies has allowed most patients to initially achieve a PASI 75 response [3]. A significant proportion of patients, however, lose their treatment response over time. Loss of response is important because psoriasis is a chronic disease that frequently develops in young adults and requires years of treatment. We focus on unmet therapeutic needs in psoriasis and identify new therapies in development to address these needs of psoriasis patients.

Efficacy Induction therapy Several biologics are available for use in moderate-tosevere plaque psoriasis, including tumor necrosis factor EJD, vol. 24, n◦ 5, September-October 2014

(TNF) blockers adalimumab, etanercept and infliximab, as well as the anti-interleukin (IL)-12/23 monoclonal antibody, ustekinumab. Biologics target specific cytokines implicated in psoriasis pathogenesis and were developed to meet the need for long-term maintenance therapy not achievable with conventional systemic agents, due to efficacy or safety limitations. In randomized controlled trials, similar PASI 75 rates at the end of induction therapy (10-16 weeks) were produced by anti-TNF monoclonal antibodies adalimumab (71%-80%) [5, 6] and infliximab (70%-80%) [7, 8], as well as ustekinumab (66%-76%; [9, 10], table 1). In contrast, the TNF-receptor Fc fusion protein etanercept (50 mg twice weekly) was less effective, producing a PASI 75 response in ∼50% of patients [11, 12]. Ninety percent decrease from baseline in PASI score (PASI 90) with each biologic was correspondingly lower: 45%-51% with adalimumab [5, 6], 37%-57% with infliximab [7, 8], 37%51% with ustekinumab [9, 10] and ∼20% with etanercept [11, 12]. Information about comparative efficacy among biologics and traditional systemic agents remains limited due to the lack of “head-to-head” trials. In the ACCEPT trial, ustekinumab 45 and 90 mg administered at baseline and Week 4 produced higher PASI 75 rates at Week 12 (68% and 74%, respectively) than etanercept 50 mg twice weekly (57%) [13]. Other studies found adalimumab and infliximab to be more effective than methotrexate, with respective PASI 75 rates at Week 16 of 80% vs. 36% in the CHAMPION trial and 78% vs. 42% in the RESTORE1 trial [8, 14]. A

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To cite this article: Kragballe K, van de Kerkhof PCM, Gordon KB. Unmet needs in the treatment of psoriasis. Eur J Dermatol 2014; 24(5): 523-32 doi:10.1684/ejd.2014.2403

Table 1. PASI response rates during induction and maintenance therapy with currently available biologics Induction therapy (placebo controlled)

Maintenance therapy (not controlled)

Study

Regimen (n)

Time point

PASI 75/90

Regimen (n)

Time point

PASI 75/90

EXPRESS: Reich et al. [7]

Infliximab 5 mg/kg at baseline and Wk 2 and 6 (301) Placebo (77)

Wk 10

80%/57%

5 mg/kg q8wk (281)

Wk 50

61%/45%a

Infliximab 3 mg/kg at baseline and Wk 2 and 6 (313) Infliximab 5 mg/kg at baseline and Wk 2 and 6 (314) Placebo (208)

Wk 10

3 mg/kg q8wk (128) 3 mg/kg prn q4-8wk (126) 5 mg/kg q8wk (134) 5 mg/kg prn q4-8wk (134)

Wk 50

44%/25%b 25%/10% 54%/34% 38%/10%

Adalimumab 80 mg at baseline, then 40 mg q2wk starting at Wk 1 (814) Placebo (398)

Wk 16

Adalimumab [dose as above] (108) Methotrexate 7.5-25 mg/wk (110) Placebo (53)

Wk 16

Etanercept 25 mg qwk (160) Etanercept 25 mg twice/wk (162) Etanercept 50 mg twice/wk (164) Placebo (166)

Wk 12

25 mg qwk (160) 25 mg twice/wk (162) 50 mg twice/wk (164)

Wk 24

25%/6%d 44%/20% 59%/30%

Etanercept 25 mg twice/wk (196) Etanercept 50 mg twice/wk (194) Placebo (193)

Wk 12

25 mg twice/wk (196) Switched from 50 to 25 mg twice/wk (194)

Wk 24

45%/NRd 54%/NR

Ustekinumab 45 mg at baseline, Wk 4 (255) Ustekinumab 90 mg at baseline, Wk 4 (256) Placebo (255)

Wk 12

45 mg q12wk (250) 90 mg q12wk (243)

Wk 28

71%/49%b 79%/56%

Ustekinumab 45 mg at baseline, Wk 4 (409) Ustekinumab 90 mg at baseline, Wk 4 (411) Placebo (410)

Wk 12

45 mg q12wk (397) 90 mg q12wk (400) Patients with PASI 75 at Wk 28 continued treatment; responses reported as “generally sustained” at Wk 52; median improvement in PASI from baseline: 95%

Wk 28

EXPRESS II: Menter et al. [8]

REVEAL: Menter et al. [5]

CHAMPION: Saurat et al. [6]

Leonardi et al. [11]

Papp et al. [12]

PHOENIX 1: Leonardi et al. [9]

PHOENIX 2: Papp et al. [10]

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3%/1% 70%/37% 76%/45% 2%/1% 71%/45%

7%/2%

80%/51%

Patients with PASI 75 responses at Wk 33 randomized to adalimumab 40 mg q2wk or placebo; loss of adequate responsec lower in patients continuing adalimumab No maintenance period

36%/14% 19%/11% 14%/3% 34%/12% 49%/22% 4%/1% 34%/11% 49%/21% 3%/1% 67%/42% 66%/37% 3%/2% 67%/42% 76%/51% 4%/1%

70%/45% 79%/54%

EJD, vol. 24, n◦ 5, September-October 2014

Table 1. (Continued) Induction therapy (placebo controlled) Study

Regimen (n)

Time point

ACCEPT: Griffiths et al. [13]

Ustekinumab 45 mg at baseline, Wk 4 (209) Ustekinumab 90 mg at baseline, Wk 4 (347) Etanercept 50 mg twice/wk (347)

Wk 12

Maintenance therapy (not controlled)

PASI 75/90

Regimen (n)

68%/36% 74%/45% 57%/23%

Time point

PASI 75/90

No maintenance period; treatment interrupted at Wk 12 in responders (additional dose of ustekinumab given at Wk 16 in non-responders), and resumed on recurrence

PASI, Psoriasis Area and Severity Index; NR, not recorded.a Values based on patients entering maintenance phase; b Values based on patients evaluated at endpoint; c PASI rates not reported; loss of adequate response defined as