There are now several biological agents available for the treatment of patients with moderate-to-severe psoriasis (Table
1). Etanercept, infliximab, adalimumab, and ustekinumab have all been shown to be effective, easing symptoms and improving QoL [
56]. Secukinumab has recently been added to the list of approved biologicals for the treatment of plaque psoriasis [
16,
17]. Compared with conventional systemic treatments, biologic drugs have reduced toxicity, lack of drug interactions, and fewer contraindications [
56,
57].
Table 1
Summary of biologic agents approved in Europe for use in moderate-to-severe psoriasis [
84]
Adalimumab | Treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen ultraviolet A Also for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age who have had an inadequate response to or are inappropriate candidates for topical therapy and phototherapies |
Efalizumab | Withdrawn |
Etanercept | Treatment of adults with moderate to severe plaque psoriasis who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy, including cyclosporine, methotrexate or psoralen and ultraviolet-A light Also for the treatment of chronic severe plaque psoriasis in children and adolescents from the age of 6 years who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies |
Infliximab | Treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen ultraviolet A |
Secukinumab | Treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy |
Ustekinumab | Treatment of moderate-to-severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate and psoralen ultraviolet A |
The licensed indication for etanercept, infliximab, adalimumab, and ustekinumab is ‘treatment of patients with moderate to severe chronic plaque psoriasis who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate, and psoralen with ultraviolet-A light (PUVA)’ [
56,
58]. However, as ustekinumab was introduced later than the tumor necrosis factor antagonists, and due to the limited experience with this agent relative to other biologicals, it has been recommended as second-line biologic therapy for psoriasis by the British Association of Dermatologists [
58]. There have been three cases of confirmed progressive multifocal leukoencephalopathy with efalizumab, with consequent withdrawal of the European marketing authorization for this agent by the European Medicines Agency (EMA) [
58].
New Therapeutic Approaches
Until recently, biological drugs were indicated in moderate-to-severe psoriasis where there was no response to, and/or the presence of intolerance or contraindications to, traditional systemic therapies. However, this has now changed with the EMA and US Food and Drug Administration (FDA) approval in January 2015 for secukinumab as first-line systemic treatment of moderate-to-severe plaque psoriasis patients [
16,
17].
Secukinumab is a first-in-class fully human anti-interleukin (IL)-17 monoclonal antibody [
59‐
61]. Secukinumab targets the IL-17A ligand and acts by inhibiting the interaction of the IL-17A ligand with its receptor, which is expressed on various cell types [
60]. This inhibits release of pro-inflammatory cytokines, chemokines, and mediators of tissue damage, reducing IL-17A-mediated processes involved in autoimmune and inflammatory diseases such as psoriasis. Secukinumab is the first biological drug approved for the first-line treatment of patients eligible for systemic therapy; all other available biological agents for psoriasis are approved as second-line systemic therapy.
The efficacy of secukinumab for moderate to severe plaque psoriasis is supported by the findings of the ERASURE (
n = 738) and FIXTURE (
n = 1306) trials (ClinicalTrials.gov identifiers: NCT01365455 and NCT01358578, respectively), both of which were 52-week phase III trials, the first one placebo-controlled and the second one with an active comparator (etanercept) [
62]. In these trials, secukinumab was given as a 300-mg or 150-mg dose once weekly for 5 weeks, then once every 4 weeks. Secukinumab was superior to placebo for the co-primary endpoints of ≥75% reduction in PASI (PASI 75) and a score of 0 or 1 on a 5-point modified investigator global assessment scale (Table
2). Two additional placebo-controlled randomized trials, JUNCTURE (
n = 182) [
63] and FEATURE (
n = 177; ClinicalTrials.gov identifiers: NCT01636687 and NCT01555125, respectively) [
64], evaluated the efficacy of secukinumab 300 mg or 150 mg administered with an autoinjector or prefilled syringe on moderate to severe psoriasis. In these trials, secukinumab was given once weekly up to week 4, then every 4 weeks, with findings again supporting the efficacy of secukinumab (Table
2).
Table 2
Summary of key phase III clinical trial data for secukinumab
| PASI 75 | 200/245 (81.6%) | 174/243 (71.6%) | 11/246 (4.5%) | | |
Response of 0 or 1 on modified IGA | 160/245 (65.3%) | 125/244 (51.2%) | 6/246 (2.4%) | | |
| PASI 75 | 249/323 (77.1%)* | 219/327 (67.0%) | 16/324 (4.9%) | 142/323 (44.0%) | |
Response of 0 or 1 on modified IGA | 202/323 (62.5%) | 167/327 (51.1%) | 9/324 (2.8%) | 88/323 (27.2%) | |
| PASI 75 | 44/59 (75%) | 41/59 (69%) | 0/59 (0%) | | |
Clear or almost clear on modified IGA | 40/59 (68%) | 31/59 (53%) | 0/59 (0%) | | |
| PASI 75 | 52/60 (87%) | 43/61 (70%) | 2/61 (3%) | | |
Clear or almost clear on modified IGA | 44/60 (73%) | 32/61 (52%) | 0/61 (0%) | | |
| PASI 90 (week 16) | 264/334 (79.0%)** | | | | 193/335 (57.6%) |
Importantly, in the FIXTURE trial the efficacy of secukinumab was compared with etanercept, and it was found that secukinumab was significantly more effective than subcutaneous etanercept 50 mg administered twice weekly with respect to the co-primary efficacy end points of PASI 75 and a response of 0 or 1 on the modified investigator’s global assessment at week 12 [
62]. Furthermore, the CLEAR trial (
n = 676; ClinicalTrials.gov identifier: NCT02074982), a 52-week, multicenter, randomized, double-blind study, compared secukinumab 300 mg, administered weekly for up to 4 weeks then every 4 weeks until week 48, with ustekinumab, with results revealing secukinumab to be significantly superior [
65]. Overall, the safety profile of secukinumab has been shown to be comparable with those of etanercept and ustekinumab. In the FIXTURE study, the number of adverse events per 100 patient-years was similar in patients receiving secukinumab 300 mg, secukinumab 150 mg, or etanercept (252.0, 236.4, and 243.4 cases per 100 patient-years, respectively), as was the number of serious adverse events (6.8, 6.0 and 7.0 cases per 100 patient-years) and the number of patients who discontinued due to adverse events (
n = 14, 10, and 12) [
62]. In the CLEAR study, 64.2% and 58.3% of patients receiving secukinumab or ustekinumab experienced at least one adverse event, and 3% of each treatment group experienced a serious adverse event [
65]. A significantly higher proportion of the secukinumab group versus the ustekinumab group in the CLEAR study self-reported no impairment of HRQoL scores due to skin impairment at week 16 (71.9% vs. 57.4%;
P < 0.0001) [
65].
Other new therapeutic approaches for the treatment of moderate-to-severe plaque psoriasis include apremilast, a phosphodiesterase-4 inhibitor, approved by the US FDA in September 2014 for use in patients who are candidates for systemic therapy [
66], with European approval in January 2015 for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to or are intolerant to other systemic therapy including cyclosporine, methotrexate, or PUVA [
67]. Apremilast has not yet been addressed in published guidelines. Other agents in development for the treatment of moderate-to-severe plaque psoriasis include brodalumab (monoclonal antibody against IL-17 receptor A), ixekizumab (a humanized anti-IL-17A antibody) [
60], guselkumab and tildrakizumab (antagonists of the p19 subunit of IL-23) [
68], and tofacitinib (a Janus kinase inhibitor) [
69]. In the AMAGINE phase III clinical trials of brodalumab (AMAGINE-I, -II, and -III, ClinicalTrials.gov identifiers: NCT01708590, NCT01708603, and NCT01708629, respectively), there was some suggestion of an increase in suicide/suicide ideation [
70,
71]; on May 22, 2015, Amgen announced that it would terminate its participation in the development of brodalumab because of these events [
72], and the AMAGINE clinical trials have been terminated.
Cost Effectiveness of the Biological Agents
Biologicals are an important option in moderate-to-severe plaque psoriasis, but are associated with significant costs and are a considerable strain for the national health systems (NHSs) of various countries. For this reason, many countries have strict criteria for refunding the cost of biologicals. In Italy the expenditure for biologicals used in psoriasis, rheumatic diseases, and oncology represents 13.7% of the drug expenditure for the NHS [
37].
Various estimates of annual costs of these therapies have been found to range between US$13,000 and US$30,000 in one study [
73], with a more recent study providing estimates of annual treatment costs with biological agents ranging from US$6800 for low-dose alefacept (no longer marketed) to US$56,000 for high-dose ustekinumab [
74]. Another study estimated the cost of 1 year of induction and maintenance treatment to be as follows: ustekinumab US$53,909; etanercept US$46,395; and adalimumab US$39,041 [
75]. In a recent review of data from high-quality randomized trials (
n = 27), cost-effectiveness ratios (determined over a 12-week period) were calculated as cost per patient achieving a PASI 75 response and the cost per patient achieving the minimal important difference in the DLQI score [
74]. In this study, intravenous infliximab 3 mg/kg was the most cost-effective biologic agent (Table
3). Although costs of biologics are higher, adherence rates are better and patients require fewer hospitalizations with biologic therapy versus non-biologics; a longitudinal cohort study of 186 patients with psoriasis in the US showed that adherence rates were 0.66 with biologics versus 0.35 with other psoriasis medications (
P < 0.001), and the mean number of hospitalizations was reduced from 0.9 in the 6 months before starting biologics to 0.4 in the 6 months after patients started therapy with biologics (
P < 0.001) [
76]. Italian-based studies have shown that hospitalization costs constitute a significant proportion of total costs; in one study, hospitalization costs were >80% of total costs, and more than 90% of the cost of physician visits, day hospital stays, and hospitalizations were incurred by the 20% of patients who were hospitalized [
77]. In another study of Italian patients with moderate-to-severe psoriasis, hospitalization cost was the most significant direct cost associated with treatment, accounting for 30% of total costs [
45]. A cost-utility analysis of psoriasis treatment in Italy has shown that etanercept treatment is a cost-effective therapy from the health service perspective and that the cost-effectiveness of etanercept increases with disease severity (incremental cost-effectiveness ratios for moderate-to-severe and severe psoriasis: €33,216 and €25,486 per QoL year, respectively) [
78]. A study of adherence to therapy with infliximab, adalimumab, or etanercept in Italian patients with psoriasis, rheumatoid arthritis or Crohn’s disease showed that non-pharmacological costs were reduced in patients who were adherent to therapy versus those who were not (€988 vs. €1255). Taken together, these data suggest that the use of biological therapies to treat psoriasis in Italy reduces healthcare costs.
Table 3
Summary of cost-effectiveness analyses of biological agents for psoriasis based on US pricing [
75]
Copyright © Cheng J, Feldman SR. Reproduced with permission from Drugs in Context. DOI:
10.7573/dic.212266
| 16 studies (1966–2004) | Annual cost (AWP, treatment administration, adverse-event monitoring and treatment, reimbursement rate from Medicare) | PASI% between 6 and 14 weeks | Infliximab 5 mg/kg at weeks 0, 2, and 6 |
| 3 RCTs | 18 months of treatment (AWP, office fees, injection fees, costs due to adverse events, laboratory monitoring) | PASI-75 at 18 months | Etanercept 50 mg twice weekly × 12 weeks, then 50 mg weekly |
| 16 studies | Annual cost (treatment administration, adverse-event monitoring and treatment) | PASI% (treatment period not specified) | Infliximab 5 mg/kg |
| 13 RCTs (1998–2004) | 12 weeks of treatment (AWP, physician visits, laboratory tests, Medicare fee for schedule of infusions) | PASI-75 after 12 weeks | Infliximab 5 mg/kg |
| 11 RCTs (2003–2007) | 12 weeks of treatment (AWP, physician visits, laboratory testing, Medicare fee for schedule of infusions) | PASI-75, DLQI after 12 weeks | Etanercept 25 mg once weekly (DLQI MID) Infliximab 3 mg/kg (PASI 75) |
| 22 RCTs (1966–2008) | Annual cost (WAC, adverse event monitoring and treatment, Medicare fee for schedule of infusions) | PASI-75, PGA 0/1 after 6–14 weeks of treatment | Infliximab 5 mg/kg at weeks 0, 2, 6, then every 8 weeks |
| 22 RCTs (2001–2011) | Annual cost (AWP, office visits, laboratory tests, monitoring procedures) | PASI-75, DLQI MID after 12 weeks of treatment | Infliximab 5 mg/kg every 8 weeks (PASI and DLQI) |
| 22 RCTs | 10–16 weeks of treatment (AWP, treatment administration, monitoring, laboratory tests) | PASI between 10–16 weeks | Adalimumab 40 mg every other week (QALY) |
| ACCEPT trial (ustekinumab, etanercept) | 16 weeks of treatment (WAC) | PASI-75 after 12 weeks | Ustekinumab (45 mg or 90 mg depending on weight) |
| ACCEPT trial (ustekinumab, etanercept) | 3 years of treatment (Medicare Part B average sales price, treatment of adverse events, physician visits) | PASI after 12 weeks | Ustekinumab 45 mg ($150,000 threshold per QALY) |
| 27 RCTs (1995–2012) | 12 weeks of treatment (AWP, physician visits, laboratory tests, Medicare fee for schedules of IV procedures) | PASI-75, DLQI after 12 weeks | Infliximab 3 mg/kg (PASI 75 and DLQI) |
| 13 RCTs (2005–2012) | 6 months of treatment (AWP) | PASI-75 and PGA 0/1 after 6 months | Adalimumab 80 mg loading dose, then 40 mg every other week (PASI 75 and PGA 0/1) |