On-Label Usage Profile
Apremilast is an orally administered, small-molecule inhibitor of phosphodiesterase 4. Small-molecule inhibitors are a class of medications with low molecular weight, high stability, and short half-life. They act intracellularly to modulate proinflammatory states through regulation of the proinflammatory cytokine milieu.
Apremilast has been approved by the FDA for use in adult psoriasis and psoriatic arthritis since 2014 and for use in treating oral ulcers of Behçet disease since 2019.1-3,5,6 Recently, a phase 2, multicenter, open-label study on the use of apremilast in pediatric psoriasis patients (aged 12–17 years) demonstrated a similar safety profile with weight-based dosing8; phase 3 trials in this population are in the recruitment phase (ClinicalTrials.gov Identifier NCT03701763).
Because information regarding its use in pregnancy is limited, apremilast is not recommended in this population. It is unknown whether apremilast is present in breast milk; although the manufacturer does not make explicit recommendations regarding use during breastfeeding, an expert panel reviewing management of psoriasis in pregnant and breastfeeding women recommended avoiding its use while breastfeeding.9
Common Adverse Effects
Common adverse effects (AEs) include weight loss (>5% total body weight in 5% of patients; 5%–10% of total body weight in 10%–12% of patients; and ≥10% total body weight in 2% of patients), diarrhea and nausea, headache, and upper respiratory tract infection.10,11 Gastrointestinal AEs tend to be self-limited and improve or resolve after the first few weeks of therapy. Caution is advised in patients older than 65 years and in those at risk for hypotension or volume depletion. Although depressed mood is a rare AE (<1%), apremilast should be used cautiously in patients with a history of depression or suicidal ideation. Weight loss generally is self-limited; routine monitoring of weight is recommended.11
Apremilast in Psoriasis and Psoriatic Arthritis
Psoriasis
The ESTEEM trials established the safety and efficacy of apremilast for use in psoriasis.2,3 In a phase 3, multicenter, double-blind, placebo-controlled trial of 844 patients, apremilast demonstrated a statistically significant 75% or greater reduction from the baseline psoriasis area and severity index score (PASI-75) in 33.1% of patients receiving the medication compared to 5.3% of those receiving placebo.2 Data from real-world practice (outside constraints of clinical trials) suggest slightly greater efficacy than was demonstrated in the ESTEEM trials.
A recently published retrospective, cross-sectional study of 480 patients with psoriasis treated with apremilast reported that 48.6% of patients continuing therapy for a mean (SD) of 6 (1) months achieved PASI-75. Furthermore, the mean dermatology life quality index (DLQI) score of the surveyed population decreased from 13.4 at initiation of treatment to 5.7 at 6 (1) months of treatment—a marked improvement in quality of life.12 Other single-center and smaller study populations also have suggested increased real-world benefit.13,14
Nonetheless, the rate and degree of clearance of plaques with apremilast seem to lag behind what is observed with many of the biologics and traditional medications employed to treat psoriasis.15-19 Furthermore, indirect cost analysis comparisons suggest a much higher cost per level of PASI for apremilast compared to several biologics and to methotrexate.20,21 A study that used indirect methods of comparison to analyze the comparative cost and efficacy of apremilast and methotrexate found no evidence of greater efficacy for apremilast and that the incremental cost to achieve 1 additional PASI-75 responder by using apremilast is $187,888 annually.21
Psoriatic Arthritis
The PALACE clinical trials 1, 2, and 3 assessed the efficacy of apremilast in patients who had prior treatment with conventional disease-modifying antirheumatic drugs or biologics, or both. PALACE 4 evaluated efficacy in treatment-naïve patients; standard dosing of apremilast was found to produce improvement in psoriatic arthritis in treatment-naïve and non–treatment-naïve patients.4-6,22 In the 24-week placebo-controlled phase of the PALACE 1 trial, the American College of Rheumatology (ACR) baseline composite measurement of 20% disease improvement, or ACR20, was achieved in 40% of patients randomized to the standard dosing regimen compared to 19% of patients receiving placebo, a statistically significant result (P<.001).22
Evaluation of long-term study data is beyond the scope of this review, but those data suggest that disease outcomes continue to improve the longer therapy is utilized, with a greater percentage of patients achieving ACR20 as well as ACR50 (50% improvement) and ACR70 (70% improvement) responses. Indirect comparisons analyzing the cost and effectiveness for adalimumab, apremilast, and methotrexate in patients with psoriatic arthritis found that apremilast was less effective than adalimumab and as efficacious as methotrexate, though apremilast carries the highest price tag of these drugs.23