Biologics in moderate-to-severe plaque psoriasis

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

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approved by the Food and Drug Administration in 2003 (although never granted a license in Europe), was voluntarily withdrawn from the US market in 2011.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.

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).

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 trial13 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, secukinumab15 and ixekizumab16 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 agents17 and currently holds data on nearly 7000 patients. Similar registers have been established, for example, Psonet18 in Europe and PSOLAR19 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.

References

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2. Smith CH et al.  British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009;161:987–1019.
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