Melinda Gooderham, MD, MSc, FRCPC1,3 and Kim Papp, MD, PhD, FRCPC2,3
1Skin Centre for Dermatology, Peterborough, ON, Canada
2K. Papp Clinical Research, Waterloo, ON, Canada
3Probity Medical Research, Waterloo, ON, Canada
Phosphodiesterase 4 (PDE4) is a key enzyme in the regulation of immune responses of inflammatory diseases through degradation of the second messenger, cyclic adenosine 3′,5′-monophosphate (cAMP). Apremilast (APR), a selective PDE4 inhibitor, has been shown to reduce the production of pro-inflammatory cytokines by increasing intracellular levels of cAMP and promoting the production of anti-inflammatory cytokines. The efficacy and safety of APR in the treatment of psoriasis and psoriatic arthritis has been demonstrated in phase 2/3 studies and is reviewed here. Across all studies, treatment was generally well-tolerated with some mild gastrointestinal complaints that occurred early and resolved over time. Meaningful improvement of psoriasis and psoriatic arthritis including dactylitis and enthesitis were observed. Routine monitoring is not required given the absence of drug associated physiologic, biochemical, and haematological changes. APR proves to be a new promising systemic therapy for treating psoriatic disease.
- Psoriasis is an immune mediated disease involving skin, joints, and possibly the bowel.1-4
- Recent clinical studies have shown precise blockade of phosphodiesterase 4 (PDE4) to be effective in the treatment of psoriasis5 and PsA.6,7
- PDE4 belongs to the phosphodiesterase family of enzymes involved in the breakdown of cyclic adenosine 3′,5′-monophosphate (cAMP).8,9
- Increase in cAMP leads to a cascade of cellular events resulting in a reduction of inflammatory mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-23, and IL-17, as well as increase in anti-inflammatory cytokines such as IL-10.8,9,10
- Inhibition of PDE4 leads to an increase in the intracellular cAMP concentration, thereby reducing the production of inflammatory mediators and increasing anti-inflammatory mediators.8,11
PDE4 Inhibitor in the Treatment of Psoriasis
- Apremilast (APR, CC-10004, Otezla™), a PDE4 inhibitor, has been shown to block the production of pro-inflammatory cytokines that play a major role in the pathogenesis of psoriasis.
- APR demonstrated a range of anti-inflammatory effects on a variety of cell lines in vitro,11 and biologic activity in a pilot study in humans.12
- APR has been evaluated in a number of phase 25,13,14 and phase 3 clinical trials (Efficacy and Safety Trial Evaluating the Effects of APR in Psoriasis [ESTEEM] 1 and 2 and LIBERATE), demonstrating efficacy in psoriasis15-17 and psoriatic arthritis (PsA).6,7,19-21
Apremilast Use in Psoriasis
Results from Phase 3 Studies in Plaque Psoriasis
- Efficacy and safety of APR 30 mg BID was evaluated in two phase 3 randomized, placebo-controlled studies ESTEEM 115 and ESTEEM 216 and compared with etanercept and placebo (PBO) in a phase 3b study (LIBERATE)17, the results of which are not described here.
- In ESTEEM1, 844 patients with plaque psoriasis (Psoriasis Area Severity Index (PASI) ≥12, Body Surface Area [BSA] ≥10%, static Physicianâ€™s Global Assessment [sPGA] ≥3) were randomized 2:1 to APR 30 mg BID (n=562) or PBO (n=282) for the first 16 weeks. See Figure 1 for study design after week 16.15
- In ESTEEM 2, 413 similar patients with psoriasis were randomized to PBO (n=138) or APR 30 mg BID (n=275) through Week 16. See Figure 1 for study design after Week 16.16
Figure 1.ESTEEM 1 and 2 study design15,16
aDoses of APR were titrated during the first week of administration.
bA responder was defined as a patient achieving ≥PASI-75 (ESTEEM 1) or ≥PASI-50 (ESTEEM 2) at Week 32.
cIn ESTEEM 1, patients were switched to APR at the time of loss of PASI-75, but no later than Week 52
In ESTEEM 2, patients were switched to APR at time of loss of effect, defined as time of loss of 50% of the PASI improvement obtained at Week 32 compared with baseline, but no later than Week 52.
dAt Week 32, patients will have the option of adding topical and/or UVB therapy. The decision may be made at Week 32 only, but does not need to be initiated at this visit. T = topicals; P = UVB phototherapy.
- Significant improvements with APR 30 mg BID were observed at Week 16 for PASI-75 (a reduction of ≥75% in PASI scores) and sPGA scores.
- In ESTEEM 1, significantly more patients in the APR group achieved PASI-75 (33.1%), PASI-50 (58.7%) and sPGA 0-1 (21.7%) vs. PBO (*P<0.0001, all),15 (Figure 2A)
- In ESTEEM 2, patients treated with APR achieved PASI-75 (28.8%), PASI-50 (55.5%) and sPGA 0-1 (20.4%) vs. PBO (*P<0.0001, all).16 (Figure 2B)
Figure 2A and 2B.PASI-75 (primary endpoint), PASI-50, and sPGA response at Week 1615,16
Patients achieving PASI-75, PASI-50, and sPGA response with APR 30 mg BID vs. PBO. A. Response at Week 16 in ESTEEM 1. B. Response at Week 16 in ESTEEM 2. sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline. *P
- For the subgroup of patients who received APR 30 mg BID from Day 0 and continued on therapy, with PASI-75 responders at Week 32, there was a mean percent change from baseline in PASI score of -80% at Week 52.15
- Improvements with APR 30 mg BID were also seen in nail, scalp and palmoplantar psoriasis as well as quality of life and pruritus.15,16,18
- Patients treated with APR 30 mg BID achieved a 50% improvement in the Nail Psoriasis Severity Index (NAPSI-50) response at Week 16 vs. PBO. In ESTEEM 1, 33.3% of APR patients achieved NAPSI-50 response vs. 14.9% PBO (P<0.0001),15 and in ESTEEM 2, 44.6% of APR patients achieved NAPSI-50 vs. 18.7% PBO (P<0.0001).16
- Patients in the APR 30 mg BID group achieved significant scalp improvement, with ScPGA 0-1 (Clear-Minimal) at Week 16 vs. those in the PBO group. In ESTEEM 1, 46.5% APR vs. 17.5% PBO (P<0.0001),15 and in ESTEEM 2, 40.9% APR vs. 17.2% PBO (P<0.0001)16.
- Palmoplantar psoriasis also improved. In ESTEEM 2, 65.4% of patients treated with APR 30 mg BID achieved PPPGA 0-1 (Clear-Minimal) vs. 31.3% of patients treated with PBO.16
- APR 30 mg BID was associated with an improvement in quality of life with significantly higher proportion of patients who achieved clinically important differences in the Dermatology Life Quality Index (DLQI) and pruritus VAS from baseline at Week 16.
- In ESTEEM 1, 70.2% of patients in the APR group achieved a clinically significant improvement in DLQI response vs. 33.5% with PBO (P<0.0001),15,22 and in ESTEEM 2, 70.8% of patients treated with APR achieved a significant DLQI response vs. 42.9% with PBO (P<0.0001).23
- For pruritus VAS, 70.6% of patients in ESTEEM 1 treated with APR achieved significant improvement vs. 33.7% with PBO (P<0.0001) in ESTEEM 1.22
Safety and Tolerability Profile
- APR demonstrated an acceptable safety profile and was generally well-tolerated for up to 52 weeks as most adverse events (AEs) were mild or moderate in severity.
- Discontinuation rates for diarrhea and nausea were each <2% in the APR 30 mg BID group through Week 52.15,16
- The most frequently reported AEs during the PBO-controlled period and APR-exposure period were diarrhea, upper respiratory tract infection (URTI), nausea, nasopharyngitis, tension headache, and headache.15,16
- Serious AEs – including serious infections, malignancies, and cardiovascular events – and laboratory value changes were not significantly affected.
- AEs in ≥5% reported during Weeks 0-16 and Weeks 0-52 in ESTEEM 1 are shown in Table 1.15 AEs reported during Weeks 0-16 in ESTEEM 2 are shown in Table 2.16
|Patients (%)||Placebo-Controlled Period Weeks 0-16||Apremilast-Exposure Period Weeks 0-52|
|Placebo n=282||Apremilast 30 mg BID n=560||Apremilast 30 mg BID n=804|
|Table 1. Adverse events ≥5% any treatment group in ESTEEM 117|
The apremilast-exposure period (Weeks 0-52) included all patients who received apremilast 30 mg BID, regardless of when treatment was initiated.
Exposure-adjusted incidence rate (EAIR) per 100 patient-years is defined as 100 times the number (n) of patients reporting the event divided by patientyears
within the phase (up to the first event start date for patients reporting the event).17
|Patients (%)||Placebo-Controlled Period|
|Placebo n=136||Apremilast 30 mg BID n=272|
|Table 2. Adverse events ≥5% any treatment group in ESTEEM 218|
APR Use in Psoriatic Arthritis
Results from Phase 3 Studies in Psoriatic Arthritis
- Efficacy and safety of APR were evaluated in four phase 3 trials in the Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical program in patients with PsA.6,7,9,19-21
- Key inclusion criteria in PALACE 1,2 were adults with a documented diagnosis of PsA at baseline (duration ≥6 months; met the Classification Criteria for Psoriatic Arthritis [CASPAR] criteria), ≥3 swollen and ≥3 tender joints despite past or current disease-modifying antirheumatic drugs (DMARDs) and/or biologics.6,7,19 In PALACE 3, patients also had at least one psoriatic lesion ≥2 cm, and in PALACE 4, DMARD and/or biologics naïve patients were included.20,21 Study design for the PALACE clinical trial program is shown in Figure 3.20
- The results of a 24-week PBO-controlled phase of PALACE 1 have been published, as well as the 52-week period results.6,7
- In PALACE 1, patients with active PsA (n=504) were randomized (1:1:1) to PBO, APR 20 mg BID or APR 30 mg BID. See Figure 3 for details.
Figure 3.PALACE Study Design6,7,19-21
p class=”p-sm”>Note: Plasma samples for the biomarker assay were obtained at baseline and Weeks 4, 16, 24, and 40.
*All doses were titrated over the first week of treatment.
§Patients whose swollen and tender joint counts had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized
(1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo. Apremilast-treated patients continued on their initial apremilast dose.
â€¡At Week 24, all remaining placebo patients were re-randomized to apremilast 20 mg BID or 30 mg BID.
- At Week 16, significantly more patients receiving APR 20 mg BID (30.4%; P=0.0166) and 30 mg BID (38.1%; P=0.0001) achieved an ACR20 response vs. PBO (19.0%).6
- At Week 24, an ACR20 response of 45.3% was observed in patients treated with APR 30 mg BID independent of their response at Week 16.6
- At Week 52, ACR20 response was observed among patients receiving APR continuously for 52 weeks (n=254) in 63.0% (20 mg BID) and 54.6% (30 mg BID) of patients.7 ACR50 and ACR70 responses were observed in 24.8% and 15.4% of patients receiving APR 20 mg BID and 24.6% and 13.8% of patients receiving APR 30 mg BID, respectively.7
- Patients treated with APR had a statistically significant improvement in physical function, as measured by changes from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score (P=0.0004 vs. PBO) and the 36-Item ShortForm Health Survey v2 Physical Functioning domain score (P=0.0001 vs. PBO).
- Significant improvements were also seen in most ACR component scores, particularly swollen and tender joint counts and patient assessment of pain (P6
- In patients with enthesitis, the mean change from baseline in the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) was significantly higher for APR 30 mg BID vs. PBO (P=0.0334), and significantly greater proportions of patients receiving APR 20 mg BID (32.0%; P=0.0037) and 30 mg BID (33.6%; P=0.0013) achieved a MASES score of 0 at Week 24 vs. PBO (14.4%).6
- In patients with dactylitis, mean change from baseline in dactylitis severity score was higher with APR vs. PBO. Greater proportions of patients with dactylitis achieved scores of 0 at Week 24 with APR 20 mg BID (50.9%), APR 30 mg BID (47.7%) vs. PBO (40.9%); these differences did not reach statistical significance at Week 24.6
- At Week 52, in patients who received APR continuously from baseline, the median change in MASES was 100% with APR 20 mg BID and 66.7% with APR 30 mg BID, and a MASES score of 0 was observed in 50.7% (35/69) of patients receiving APR 20 mg BID and 38.2% (34/89) receiving APR 30 mg BID.7
- AEs in the PALACE 1 trial were similar to the psoriasis studies with gastrointestinal, mild or moderate in severity, occurred early, self-limited, did not recur, and infrequently led to discontinuation (<2.5%) through Week 24.7
- No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.
- For an overview of AEs occurring in ≥5% of PALACE 1 see Table 3.
|Patients (%)||Placebo-Controlled Period|
|n=168||20 mg BID n=168||30 mg BID n=168||20 mg BID n=245||30 mg BID n=245|
|Upper respiratory tract infection||3.6||6.0||4.2||7.8||5.7|
|Table 3. Adverse events ≥5% any treatment group in PALACE 17|
Warning and Precautions: Data from Studies in Psoriasis and PsA
- During the controlled period of the trials, weight decrease between 5%-10% of baseline body weight was reported in 12% of psoriasis and 10% of PsA patients treated with APR 30 mg BID vs. 3-5% treated with PBO. Weight decrease of ≥10% of body weight occurred in 2% of patients treated with APR 30 mg BID vs. 1% in the PBO group.
- It is recommended that patients treated with APR should have their weight monitored regularly.24
- While treatment with APR was associated with a risk of depression, data from the clinical trials do not suggest an increase in depression nor suicidal ideation in subjects treated with APR vs. PBO.24
- Co-administration with cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) resulted in a reduction of systemic exposure of APR, which may result in a loss of its efficacy and is not recommended.24
Approval and Indications
Apremilast was approved by Health Canada in November, 2014. It is indicated for the treatment of plaque psoriasis in adult patients with moderate to severe disease who are candidates for phototherapy or systemic therapy. It is also indicated for psoriatic arthritis either alone or in combination with methotrexate, for the treatment of active arthritis in adult patients who have had an inadequate response, intolerance, or contraindication to a prior disease-modifying anti-rheumatic drug (DMARD).24 The recommended daily dosing is 30 mg PO BID. However, an initial titrated dose from 10 mg to 30 mg over the first week is recommended and is available in a convenient dosing pack.
Treatment with APR demonstrated efficacy in reducing the severity of moderate to severe plaque psoriasis15-17 and improving signs, symptoms and physical function in PsA.6,7,19-21 APR demonstrated an acceptable safety profile and was well-tolerated with generally mild GI complaints occurring early in the course of the treatment and resolving with time, and there was no requirement for laboratory monitoring.5-7,15-21 Based on these results, APR should be considered as a therapeutic option in the treatment of plaque psoriasis and PsA.
The authors gratefully acknowledge the medical editorial support from Flora Krasnoshtein in preparing the original manuscript.
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