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Abstract
▼ Apremilast (Otezla - Celgene Europe Ltd.) is a novel orally administered immunomodulatory medicine licensed for the treatment of plaque psoriasis and psoriatic arthritis.1 The company suggests that it has demonstrated proven and durable efficacy in both conditions and has a favourable safety profile with no requirement for drug-specific pre-screening or ongoing laboratory monitoring.i Here we review the evidence on the safety and efficacy of apremilast in the management of psoriasis and psoriatic arthritis.
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Background
Psoriasis is estimated to affect approximately 2% of the population in the UK.2 Plaque psoriasis is the most common form of the condition affecting about 90% of people with psoriasis and is characterised by well-demarcated red, scaly plaques that vary in extent from a few patches to widespread involvement. Psoriasis is associated with joint disease in a significant proportion of patients.3 It is thought that 5–7% of all people with psoriasis, and approximately 40% of those with extensive skin disease, have psoriatic arthritis.4
Current treatment options
For people with mild psoriasis, topical agents are used as first-line treatment and include emollients, corticosteroids, vitamin D analogues, dithranol and coal tar preparations.2,3 These agents may also be used in addition to systemic treatments in patients with more severe disease.5 Second-line therapy includes phototherapy and non-biological agents such as ciclosporin, methotrexate and acitretin. Third-line treatments include tumour necrosis factor alfa (TNFα) antagonists (e.g. adalimumab, etanercept, infliximab) and ustekinumab, which targets interleukin 12 and interleukin 23.6
In the management of psoriatic arthritis, oral NSAIDs may be used to provide short-term symptom relief with intra-articular corticosteroids used as bridging therapy while waiting for systemic treatments to exert their effect.3 The primary aim of treatment is to suppress joint, tendon and ligament inflammation, and to manage skin symptoms.4 Current guidelines encourage early diagnosis and early use of conventional oral disease modifying anti-rheumatic drugs (DMARDs), including methotrexate, sulfasalazine (off-label use) and leflunomide in order to minimise damage to joints. Although such drugs are widely used there is not a strong evidence base to guide choice or treatment sequencing, and it is recommended that prescribing decisions should take in to account the patient's preference, severity of joint disease, severity of skin disease, comorbidities and the drug's adverse effect profile.3 Third-line treatments include TNFα antagonists3 or other types of immunomodulating biological therapy (e.g. ustekinumab).
Long-term drug treatment of psoriasis and psoriatic arthritis is often compromised by adverse reactions, gradual loss of effect over time and patients' concerns relating to the use of medicines that require injection or infusion.7,8
Outcome measures
Psoriasis
The Physician's Global Assessment (PGA) of psoriasis severity score is used as a means of assessing all psoriatic lesions on a 6- or 7-point scale (from severe to none); it gives an overall evaluation of severity or improvement of psoriasis on treatment.9 The static PGA (sPGA) measures the physician's impression of the disease at a single time point. However, the European Medicines Agency (EMA) does not define a meaningful clinical response using this measure.
The Psoriasis Area and Severity Index (PASI) score combines the extent of the psoriasis with local signs of erythema, scaling and elevation (range 0–72). A score of <10 indicates mild disease, 10–20 moderate to severe disease and >20 severe to very severe disease (scores >30 are rare).9 The EMA states that the best estimate of efficacy in treatment of psoriasis is the percentage of patients that achieve a reduction in their PASI score of 90%. In severe disease a reduction of 75% may be considered to be a good response.
The EMA strongly recommends that both PASI and PGA scores are used in the assessment of medicines for psoriasis.
Psoriatic arthritis
The American College of Rheumatology (ACR) response criteria were developed for rheumatology but are also accepted for psoriatic arthritis.10 The ACR20 criteria requires a ≥20% reduction in a modified swollen joint count, and a ≥20% reduction in three out of five additional measures that include patient assessed pain, patient global assessment of disease activity, the disability index of the validated Health Assessment Questionnaire-Disability Index (HAQ-DI) and acute phase reactant. The EMA state that the magnitude of response required to be deemed clinically meaningful remains to be determined but that ACR20 is a reasonable choice of primary end-point. However, the National Institute for Health and Care Excellence (NICE) has stated that a 50% reduction (i.e. an ACR50 response) is a more clinically important outcome.11
What is apremilast?
Apremilast is a small molecule that specifically inhibits phosphodiesterase 4 (PDE-4) resulting in an elevation of cyclic-AMP levels in cells, which in turn decreases T-cell secretion of pro-inflammatory cytokines and other mediators including TNFα, interferon-gamma, nitric oxide synthase, interleukin-2, interleukin-7 and interleukin-23.12 It is thought that through the modulation of cyclic AMP levels, PDE-4 may regulate the proinflammatory actions of monocytes, T-cells and neutrophils.
In January 2015, apremilast received marketing authorisation in the UK for the treatment of moderate to severe chronic plaque psoriasis in adults who have failed to respond, have a contraindication, or are intolerant to other systemic therapies including ciclosporin, methotrexate, or psoralen and ultraviolet A light (PUVA). It is also licensed to be used alone or in combination with DMARDs for the treatment of active psoriatic arthritis in adults who have had an inadequate response or who have been intolerant to DMARD therapy. For both indications apremilast is titrated in 10mg increments over 6 days to a treatment dose of 30mg twice daily.1 The summary of product characteristics states that clinical experience beyond 52 weeks is not available.
Evidence in psoriasis
Two Phase III randomised, double-blind, placebo-controlled studies have assessed apremilast in patients with moderate-to-severe psoriasis. One of these has been fully published,13 and the results of both are reported in the Food and Drug Administration and EMA assessment documents.14,15 The trials enrolled a total of 1,257 patients with psoriasis (mean PASI score 19) who were considered candidates for phototherapy or systemic therapy. Patients were randomised to receive apremilast (titrated to 30mg twice daily over 6 days) or placebo. The primary outcome was the proportion of patients who achieved a 75% reduction in PASI score and a major secondary outcome was the proportion of patients who achieved sPGA scores of clear or almost clear at 16 weeks. Patients could continue to use topical therapeutic agents except for the day before assessment. Approximately 30% of trial participants had previously received phototherapy, 55% had received conventional systemic therapy and/or biological therapy, and about one third were treatment naive. The key results are shown in Table 1.
Key results15
A Phase III head-to-head comparison with etanercept was recently presented at conference but the results have not been fully published in a peer-reviewed journal.
Evidence in psoriatic arthritis
The safety and efficacy of apremilast has been evaluated in three randomised double-blind placebo-controlled studies (PALACE 1, PALACE 2 and PALACE 3).15 These trials involved adult patients with active psoriatic arthritis (≥3 swollen joints and ≥3 tender joints) despite prior treatment with conventional DMARDs or biological agents, and a diagnosis for at least 6 months. Patients were eligible for recruitment if they had active disease and some concomitant DMARD-based regimens were permitted. Patients were excluded from the trial if they had failed three or more DMARD treatments or more than one TNFα antagonist. A total of 1,493 patients were randomised and treated with either placebo or apremilast 20mg or 30mg twice daily. Only one trial has been published in full, but details of all three trials are available in the regulatory assessment reports.15,16 The primary outcome was the proportion of patients achieving 20% improvement in modified ACR response criteria (ACR20) at week 16. The key secondary outcome was change from baseline in HAQ-DI at week 16.
In the published study, 504 patients were randomised and received at least one dose of study medication.16 At baseline over 74% of patients had used a DMARD previously and 65% of patients were taking DMARDs along with their allocated trial treatment of whom 84% were taking methotrexate. It is reported that 24% of trial participants had previous exposure to a biological drug and 9% were considered to have failed biological treatment.
After 16 weeks, in the intention-to-treat population an ACR20 response was achieved by 38%, 30% and 19% of those taking apremilast 30mg, 20mg or placebo twice daily respectively.16 The differences between the active groups and placebo were statistically significant. This difference was also reflected in associated HAQ-DI scores and a number of other secondary outcomes including PASI-50 in the subset of patients whose baseline psoriasis affected at least 3% of their body.
A pooled analysis of the results from all three trials and selected subgroup analyses were reported in the regulatory assessment report (see Table 2).15
Pooled analysis
In a follow up to the Palace 1 study, patients whose swollen and tender joint counts had not improved by ≥20% at week 16 were re-randomised to apremilast 20mg or 30mg twice daily if they were initially randomised to placebo, or continued their initial treatment of apremilast dose. At week 24, all remaining placebo patients were re-randomised to apremilast 20mg or 30mg twice daily. Of the 254 patients who received apremilast for 52 weeks it is reported that the ACR20 response rates were 63% and 55% for apremilast 20mg and 30mg respectively.17 However, this response rate reflects a population that chose to remain on treatment beyond 16 and 24 weeks.
Strengths and weaknesses of the data
The two published trials comparing apremilast with placebo in psoriasis and psoriatic arthritis seem methodologically robust.13,16 However, we are not aware of any published data that has assessed apremilast with active controls in either indication. The data available from regulatory sources indicate that the trials conducted have been of limited duration and the trial design makes it difficult to compare the results with standard treatments.
Safety
A pooled analysis of safety data derived from over 4,000 patients treated in the clinical development programme showed that 8.4% of patients treated for psoriasis and 7.5% patients treated for psoriatic arthritis discontinued treatment because of adverse events.15 The most commonly reported adverse reactions were diarrhoea (15.7%) with 1.7% discontinuing treatment during the first 16 weeks, nausea (13.9%) with 1.5% discontinuing treatment during the first 16 weeks, upper respiratory tract infections (8.4%), headache (7.9%) and tension headache (7.2%).
As part of the risk management plan for apremilast it is recommended that patients should be monitored for early signs and symptoms of depression and that patients who are underweight should have their body weight monitored at the start of treatment.18 In the ESTEEM-1 study it was reported that the median weight loss associated with long-term use of apremilast was 1.4kg and 19% of patients showed a weight loss of over 5%.13 Treatment cessation should be considered in underweight patients who experience unexplained and clinically significant weight loss.
Other potential harms of treatment include vasculitis, risk of triggering suicidal thoughts, tumours, nervousness and anxiety, serious infections and major heart problems.18 It is stated that at present there is a lack of information to inform use in children under 18 years, patients with moderate to severe reduction in kidney function or liver function, patients taking apremilast for longer than one year, patients of non-white racial origin and patients who receive live vaccines.
Contra-indications and special warnings
Apremilast is contra-indicated in patients who are hypersensitive to the active drug or any of the excipients listed in the Summary of Product Characteristics.1 It is also contra-indicated in pregnancy as no studies have been conducted in pregnant women and animal data indicate potential problems with fetal growth and development when used at supra-therapeutic doses. Apremilast should not be prescribed to breastfeeding mothers.
Drug interactions
Co-administration of rifampicin (a strong inducer of cytochrome P450 3A4 [CYP3A4]) resulted in a reduction of systemic exposure to apremilast. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin and St. John's Wort) with apremilast is not recommended.1
What guidelines say
The Scottish Medicines Consortium has approved apremilast for use in psoriasis in line with the licensed indication19 and for use in psoriasic arthritis provided it is restricted to adult patients who have had an inadequate response to at least two prior DMARD therapies or are intolerant to such therapies.20 NICE has provisionally advised that apremilast should not be recommended for use in psoriasis21 or psoriatic arthritis11 as it was not judged to be cost effective for either indication.
Cost
The annual cost of apremilast is £7,140. This makes it less expensive than the biological therapies that are licensed for use in these conditions, which typically cost around £10,000 per year, but considerably more than conventional DMARD treatment. However, apremilast does not require any drug-specific laboratory monitoring tests.
Conclusion
▼ Apremilast is a new oral drug licensed for use in psoriasis and psoriatic arthritis for patients who have failed to respond to, or who are unable to take, other systemic treatments. Its marketing authorisation does not require any drug-specific laboratory monitoring.
Much of the data from placebo controlled clinical trials is only available in the regulatory assessment report. There is one unpublished trial that has compared apremilast with etanercept in psoriasis and we are not aware of any published trials have compared apremilast with any other form of biological therapy for psoriatic arthritis.
Based on the limited evidence available it would appear that for every four or five patients with psoriasis treated with apremilast instead of placebo for 16 weeks, one additional patient will achieve a PASI-75 response. For every five patients with psoriatic arthritis treated with apremilast instead of placebo for 16 weeks, one additional patient will achieve an ACR20 response. However, the clinical significance of such outcome measures and evidence of effectiveness beyond 16 weeks also need to be taken into account.
Apremilast appears to be reasonably well tolerated but commonly reported adverse reactions include diarrhoea and vomiting. Weight loss associated with treatment may be viewed as advantageous for some patients but problematic for others.
In the absence of any published comparative data with conventional DMARDs or biological therapies it is not possible to draw any firm conclusions on the role of apremilast in the management of psoriasis and psoriatic arthritis. Until these limitations are addressed, we feel that apremilast should be restricted to patients who would currently qualify for treatment with biological therapy but are not suitable for such treatment.