Long‐Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials

Abstract

Objective Psoriatic arthritis (PsA) requires long‐term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long‐term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3‐year apremilast safety and tolerability in PsA. Methods Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re‐randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double‐blind treatment continued to week 52; patients could continue apremilast during an open‐label, long‐term treatment phase. Results In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure‐adjusted incidence rate [EAIR]/100 patient‐years, 265.1) versus placebo (47.5%; EAIR/100 patient‐years, 200.7) in the placebo‐controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast‐exposed patients were diarrhea (13.9%; EAIR/100 patient‐years, 18.6), nausea (12.3%; EAIR/100 patient‐years, 16.0), headache (9.4%; EAIR/100 patient‐years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient‐years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient‐years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient‐years, 1.8). Major adverse cardiac events (EAIR/100 patient‐years, 0.5), malignancies (EAIR/100 patient‐years, 0.9), and serious opportunistic infections (EAIR/100 patient‐years, 0.0) were infrequent over the 3‐year exposure period. Discontinuation rates due to AEs were low (<7.5%) across all apremilast‐exposure periods. Incidences of clinically meaningful abnormalities in postbaseline laboratory values was low; most values returned to baseline levels with continued treatment and without intervention. Conclusion Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks.

Apremilast in Refractory Behçet’s Syndrome: A Multicenter Observational Study

“…Regarding the type of AE, a similar profile was reported in BS, PsA or psoriasis studies, with diarrhea, nausea, and headache accounting for the most common events ( 11 , 12 , 14 , 15 , 25 , 27 ). Although gastrointestinal side effects represented the leading symptom motivating discontinuation in our cohort, two patients (4%) interrupted apremilast because of suicidal ideation.…”

“…Indeed, a gap between clinical trials and real-life studies has been noted in other apremilast label indications. In PsA, pooled data from phase III trials reported withdrawal due to AE in 7.6% of patients over a 1-year period ( 25 ). Conversely, real-life studies have demonstrated higher rate of apremilast discontinuation ranging from 20% to 38% ( 21 , 26 ).…”

Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases

“…In PALACE I, the percentage of patients achieving ACR50 and ACR70 responses at week 24 was significantly higher in the apremilast-treated patients compared with those in the placebo group [ 58 ]. The post-hoc analysis of PALACE I–III showed that twice as many patients with moderate disease activity at baseline achieved treatment targets—clinical Disease Activity index of Psoriatic Arthritis (cDAPSA) remission or low disease activity—compared with patients with baseline high disease activity [ 52 , 59 ]. A partial response, ≥30% in cDAPSA improvement, at week 16 was associated to a greater probability to achieve the target by week 52 and patients who already achieved the target at week 16 were likely to remain at target at week 52 [ 59 ].…”

“…The pooled data on 1493 patients who received at least one dose of the study drug in the PALACE I–II–III studies reported the safety profile of apremilast. In the placebo-controlled phase, the percentage of patients in the placebo or apremilast 20 mg and 30 mg arms reporting at least one adverse event was not statistically different (47.8%, 60.5%, 61.5%, respectively); the rate of serious adverse events and the percentage of patients who withdrew from the study due to adverse events were also similar across the treated groups [ 59 ]. The rate of serious infection was 0.4% in the placebo group and 0.6% in the apremilast 30 mg twice a day group; no case of tuberculosis reactivation was reported.…”

“…Exposure-adjusted incidence rates (EAIR) was low during the first 52 weeks (0.2/100 patients-year) and remain stable until week 156 (0.4/100 and 0.5/100 patients-year from week 0 to 104 and 156, respectively) [ 52 ]. Rates of malignancies were low across the apremilast dose throughout the 156-week exposure period [ 59 ].…”