Evidence suggests that the biologics are highly effective for patients who have failed to respond to other treatment modalities for moderate-to-severe psoriasis but because relapse is common, continuous therapy is required to maintain efficacy
Rod Tucker PhD MRPharmS
Honorary Research Associate,
Faculty of Health and Social Care,
University of Hull, UK
Email: [email protected]
The biologics are the most recent addition to the therapeutic armamentarium in the management of moderate-to-severe psoriasis and the available evidence suggests they are highly effective for patients who have failed to respond to other treatment modalities.(1) Nevertheless, and irrespective of the treatment used, withdrawal of therapy in psoriasis invariably leads to a relapse, thereby necessitating continued use of treatment to maintain remission. Studies with the biologics demonstrate that continuous therapy is more effective than intermittent use and loss of efficacy, defined as a 50% reduction in the Psoriasis Area and Severity Index score (PASI 50) in those who had attained a PASI 75, varies depending on the individual agent but, on average, is about 85 days.(2)
Although both efficacious and safe, most trials of the biologics have been of relatively short duration (12–24 weeks) and given the need for continuous treatment, it remains unclear whether the therapeutic benefits observed in the short term are sustained in the long term. Early indications of problems with the long-term use of biologics was highlighted in 2009 when the European Medicines Agency withdrew the marketing authorisation for efalizumab because of the risk of developing multifocal leukoencephalopathy (PLM) and since that time, a further two patients prescribed efalizumab for over three years developed PLM and subsequently died.(3)
Available agents
There are currently four biologic agents available in the UK licensed for the treatment of moderate to severe psoriasis unresponsive to other therapies: etanercept (Enbrel®); adalinumab (Humira®); ustekinumab (Stelara®); and infliximab (Remicade®). Other biologics such as alefacep (Amivive®), which was originally approved by the Food and Drug Administration in 2003 (although never granted a license in Europe), was voluntarily withdrawn from the US market in 2011.
In recent years, the results of several open-label extension studies have become available. These trials follow-up on patients who were originally enrolled in randomised, double-blind, placebo-controlled trials, and while focused primarily on long-term safety, treatment efficacy is often included as a secondary outcome. The results of recent open-label extension studies for the licensed biologics are described below and a brief summary of the trials is given in Tables 1 and 2.
Etanercept
The longest efficacy study for etanercept was recently reported by Papp et al.(4) The study described the follow-up of a cohort of 108 patients who had originally enrolled in one or more Phase III studies for 24 weeks and who were subsequently monitored for a total of 48 months. PASI data were not recorded consistently in the trials and hence not reported as outcomes in the paper. The proportion of Dermatology Quality of Life Index (DLQI) responders and the static PGA data are shown in Box 1 below.
BOX 1
DLQI responders PGA*
week 12 week 192 week 12 week 192
74% 75% 86% 56 %
* Combined value for clear/almost clear
PGA=physician global assessment
Although a similar proportion of patients remained as DLQI responders at week 96, the reduced PGA suggests that efficacy was lost in the long term.
In contrast, other studies have shown that the response to treatment is maintained over time. In a paediatric study by Paller et al,(5) efficacy was maintained throughout the whole trial (Box 2).
BOX 2
PASI 75 DLQI Responders* PGA**
week 12 week 96 week 12 week 96 week 12 week 96
57% 61% 52% 61% 53% 47%
* A children’s DLQI was used; ** combined value for clear/almost clear
Data for the PGA at 12 weeks are not stated but was reported in the original trial.(6) However, it is worth noting that on entry to the extension trial, the mean PASI score was only 4.8 (PASI scores 10 and over are considered severe) and the proportion reported clear or almost clear on the static PGA was 44.5%. Therefore patients enrolled in the extension study effectively had mild disease.
In the study of adults by Tyring et al,(7) PGA was not recorded but PASI 75 and the proportion of DLQI responders was maintained up the end of the open label phase at week 96. The paper also reported that the open label extension was to be continued for 132 weeks though no further efficacy data appear to have been published.
Infliximab
Only one long-term trial of infliximab has been reported: RESTORE 2, which was an extension of the RESTORE 1 trial(13) and scheduled to last 128 weeks. Unfortunately due to safety concerns, RESTORE 2 was terminated early because of side effects. In fact the authors report that: “no formal efficacy analyses were conducted, the primary endpoint (PASI 75 at week 128) could not be analysed, and no definitive efficacy conclusions could be drawn.” The baseline (that is, week 26 of RESTORE 1) DLQI was reported as 1.4 for those given continuous infliximab but by week 52, the DLQI had increased to 3.0 but reduced slightly to 2.1 at week 100.
Infliximab was recently studied in small sample of Japanese patients with psoriasis for up to 66 week and efficacy was retained over time as shown below.(14) PGA was reported in the study but the results displayed graphically, so it has not been possible to provide accurate figures.
Ongoing registry data
The available open label extension trials appear to suggest that the biologic agents remain efficacious when used, in some cases for up to five years. Nonetheless, such trials are expensive and it is likely that in the future more biologic agents will become available, emphasising the need for long-term efficacy and safety data and, in fact, two agents, secukinumab(15) and ixekizumab(16) are currently undergoing Phase II and Phase III studies.
One possible solution to the provision of longer-term efficacy and safety information is establishment of pharmacovigilance registers, which collate data on the real-world experience of the biologics. While the primary focus of these registers is safety, they will also collect data on the longer-term efficacy of biologics. In the UK, the British Association of Dermatologists’ Biologic Interventions Register (BADBIR) was established in 2007 and collects a wide range of data on patients prescribed biologic agents(17) and currently holds data on nearly 7000 patients. Similar registers have been established, for example, Psonet(18) in Europe and PSOLAR(19) in the US though to date, no efficacy data from these registers has been published.
Conclusions
Biological treatments are effective for patients with moderate-to-severe disease but because relapse is common, continuous therapy is required to maintain efficacy. Safety and efficacy data provided by registers such as BADBIR and PSOLAR will hopefully re-affirm the observations from open-label extension studies that long-term use of biologics is an effective and safe treatment modality, providing reassurance to both clinicians and patients.
Key points
- Several randomised, controlled trials have demonstrated that the biologics are highly effective in moderate-to-severe psoriasis.
- Psoriasis invariably relapses once therapy is discontinued, thus requiring continuing treatment.
- Whether or not the newer agents maintain efficacy and safety in the long-term is currently unclear.
- Several open-extension trials suggest that, when used up to three years, these agents appear safe and efficacious.
- Registers such as BADBIR, PSOLAR and PSONET will provide ongoing pharmacovigilance data that should inform on the continued safety and efficacy of these agents.
References
- Reich K 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(1):179–8.
- Smith CH et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009;161:987–1019.
- Schwab N et al. Fatal PML associated with efalizumab therapy: insights into integrin αLβ2 in JC virus control. Neurology 2012;78(7):458–67.
- Papp KA et al. Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population. J Am Acad Dermatol 2012;66(2):e33–45.
- Paller AS et al. Long-term etanercept in pediatric patients with plaque psoriasis. J Am Acad Dermatol 2010;63:762–8.
- Paller AS et al. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med 2008;358(3):241–51.
- Tyring S et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 2007;143:719–26.
- Esposito M, Giunta A, Mazzotta A. Continuous treatment of plaque-type psoriasis with etanercept: an observational long-term experience. Int J Immunopathol Pharmacol 2010;23(2):503–9.
- Menter A et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol 2008;58:106–15.
- Papp K et al. Long-term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: subanalysis of REVEAL and the open-label extension study. JEADV 2013;27:634–42.
- Kimball AB et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2012;Dec 20 [Epub ahead of print].
- Igarashi A et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-to-severe plaque-type psoriasis: Long-term results from a phase 2 ⁄3 clinical trial. J Dermatol 2012;39:242–52.
- Reich K et al. Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2). Br J Dermatol 2013;168(6):1325–34.
- Torii H et al. Infliximab monotherapy in Japanese patients with moderate-to-severe plaque psoriasis and psoriatic arthritis. A randomized, double-blind, placebo-controlled multicenter trial. J Dermatol Sci 2010;59(1):40–9.
- Papp KA et al Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol 2013;168(2):412–21.
- Ren V, Doa H. Potential role of ixekizumab in the treatment of moderate-to-severe plaque psoriasis. Clin Cosmet Invest Dermatol 2013;6:75–80.
- Burden AD et al. The British Association of Dermatologists’ Biologic Interventions Register (BADBIR): design, methodology and objectives. Br J Dermatol 2012;166(3):545–54.
- Garcia-Doval I et al. Systemic psoriasis therapy shows high between-countries variation. A sign of unwarranted variation? Cross-sectional analysis of baseline data from the Psonet registries. Br J Dermatol 2013 Mar 29 [Epub ahead of print].
- Papp KA et al. PSOLAR: design, utility, and preliminary results of a prospective, international, disease-based registry of patients with psoriasis who are receiving, or are candidates for, conventional systemic treatments or biologic agents. J Drugs Dermatol 2012;11(10):1210–7.
- Carlin CS et al. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis. J Am Acad Dermatol 2004;50:859–66.
