Elsevier

The Lancet

Volume 380, Issue 9843, 25–31 August 2012, Pages 738-746
The Lancet

Articles
Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)60642-4Get rights and content

Summary

Background

Apremilast, a small-molecule inhibitor of phosphodiesterase 4, works intracellularly to modulate proinflammatory and anti-inflammatory mediator production, and doses of 20 mg twice daily have shown efficacy in the treatment of moderate to severe plaque psoriasis in a 12-week phase 2 study. We assessed the clinical efficacy and safety of different doses of apremilast in the treatment of patients with moderate to severe plaque psoriasis.

Methods

In this phase 2b, multicentre, randomised, placebo-controlled, dose-ranging study, patients (aged ≥18 years) with moderate to severe psoriasis were randomly assigned (in a 1:1:1:1 ratio) to receive oral placebo or apremilast 10, 20, or 30 mg twice daily at 35 US and Canadian sites between Sept 24, 2008, and Oct 21, 2009. At week 16, patients in the placebo group were assigned apremilast 20 or 30 mg twice daily until week 24. Randomisation was generated with a permuted-block randomisation list via interactive voice response system. For the first 16 weeks, treatment assignment was concealed from both investigators and participants. During weeks 16–24, investigators and participants all knew that treatment was active, but the dose was concealed. The primary endpoint was the proportion of patients achieving at least 75% reduction from baseline psoriasis area and severity index (PASI-75) at week 16. Analyses were by intention to treat; missing values were imputed by last-observation-carried-forward. This trial is registered with ClinicalTrials.gov, number NCT00773734.

Findings

89 patients were randomly assigned apremilast 10 mg, 87 apremilast 20 mg, and 88 apremilast 30 mg twice daily; 88 were assigned placebo. At week 16, PASI-75 was achieved in five patients (6%) assigned placebo, ten (11%) assigned apremilast 10 mg, 25 (29%) assigned 20 mg, and 36 (41%) assigned 30 mg. Apremilast 10 mg did not differ significantly from placebo in achievement of the endpoint (odds ratio 2·10; 95% CI 0·69–6·42); for both apremilast 20 mg (6·69; 2·43–18·5; p<0·0001) and apremilast 30 mg (11·5; 4·24–31·2; p<0·0001), the differences from placebo were significant. Most adverse events (96%) were mild or moderate; at least 5% of patients had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests.

Interpretation

Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis. Our results support continuing, longer-term studies.

Funding

Celgene Corporation.

Introduction

Long-term treatment of psoriasis with non-biological or biological systemic therapies is often compromised by adverse events, safety and tolerability issues, loss of effect with time, and route of administration (injection vs oral), any of which might contribute to low adherence.1, 2, 3, 4, 5, 6, 7, 8 An effective, well-tolerated, safe, and easy-to-use treatment for psoriasis is needed.

Drug development for psoriasis has targeted signalling between inflammatory cells, such as T cells and myeloid dendritic cells. Biological therapies target specific proinflammatory cytokines, such as tumour necrosis factor α (TNFα), and interleukins 12, 17, and 23.9 Phosphodiesterase 4 is an intracellular enzyme that degrades the secondary messenger cAMP, leading to increased production of proinflammatory cytokines.10, 11, 12, 13, 14, 15, 16 It is the predominant phosphodiesterase expressed in cells of the immune system, including dendritic cells, monocytes, and neutrophils; it is also expressed in keratinocytes. Phosphodiesterase 4 inhibitors are being investigated because they can modulate cAMP concentrations and the related downstream inflammatory signalling cascade.11, 12, 13, 14, 15

Apremilast (CC-10004; Celgene Corporation, Summit, NJ, USA) is a novel, orally available small molecule that specifically inhibits phosphodiesterase 4.12 In vitro, apremilast decreases production of inflammatory mediators such as TNFα, interleukins 2, 12, and 23, and c-x-c motif chemokine 10 by peripheral blood mononuclear cells, and TNFα by natural killer T cells and keratinocytes. In mice with psoriatic xenografts, apremilast reduced epidermal thickness and proliferation and decreased the severity of psoriasiform features.12 The pharmacokinetics of apremilast have been characterised (appendix p 1).17, 18, 19, 20, 21 In a phase 2, randomised, placebo-controlled study, apremilast 20 mg twice daily showed efficacy in patients with moderate to severe plaque psoriasis during 12 weeks of treatment.22 In this dose-ranging study, we assessed the clinical efficacy and safety of apremilast 10, 20, and 30 mg twice daily versus placebo in patients with moderate to severe plaque psoriasis.

Section snippets

Study design and participants

This phase 2b, randomised, multicentre, placebo-controlled, dose-ranging trial was done at 35 sites in the USA and Canada (appendix p 2) between Sept 24, 2008, and Oct 21, 2009. Patients aged 18 years or older were eligible for enrolment if they had had moderate to severe plaque psoriasis (psoriasis area and severity index [PASI] ≥12; body surface area ≥10%) for 6 months or longer and were candidates for phototherapy or systemic therapy. Individuals were excluded if they had a history of, or

Results

88 patients were assigned placebo, 89 apremilast 10 mg, 87 apremilast 20 mg, and 88 apremilast 30 mg (figure 1). Demographic and baseline characteristics were generally well balanced between treatment groups (table 1). Most patients were male, white, and obese (table 1). Patients had plaque psoriasis for a mean of 19 (SD 12) years and 21% had a history of psoriatic arthritis. The mean baseline PASI score was 18·5 and mean baseline body surface area was 22%.

The primary endpoint of PASI-75 at

Discussion

Apremilast, given orally at 20 or 30 mg twice daily, seems to be efficacious, safe, and tolerable for patients with moderate to severe plaque psoriasis. The primary endpoint of PASI-75 at week 16 was achieved by significantly more patients assigned apremilast 20 mg or apremilast 30 mg than placebo, but apremilast 10 mg did not significantly differ from placebo in efficacy. Although no statistical comparisons between apremilast doses were done, apremilast 30 mg had the most favourable outcome

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