Sustained improvement in patient-reported outcomes with continued apremilast treatment over 104 weeks in patients with moderate-to-severe psoriasis
Presenters: Chapman S1, Cirulli J2, McBride S3
Affiliations: 1Dartmouth–Hitchcock Medical Center, Lebanon, NH; 2Celgene Corporation, Summit, NJ; 3Royal Free London NHS Foundation Trust, London, UK
Background/Objective: Psoriasis is a chronic, systemic, inflammatory disease that is associated with significant impairments in quality of life (QoL), which can include physical discomfort, pruritus, and emotional distress. Apremilast is an oral, small-molecule phosphodiesterase 4 inhibitor that has demonstrated efficacy and safety versus placebo (PBO) in the LIBERATE global Phase IIIb trial in patients with moderate-to-severe plaque psoriasis. Efficacy was maintained for up to 104 weeks in patients who continued treatment with apremilast 30mg twice-daily (APR) in the LIBERATE trial. To further understand the clinical profile of APR, the effect of long-term APR treatment on patient-reported outcomes assessed at 104 weeks was evaluated in the LIBERATE patient population.
Methods: Adults 18 years of age or older with chronic plaque psoriasis for at least 12 months and who were candidates for phototherapy with no prior exposure to biologics for the treatment of psoriatic arthritis or psoriasis were included. Included patients had moderate-to-severe plaque psoriasis, as defined by Psoriasis Area and Severity Index (PASI) score 12, psoriasis-involved Body Surface Area (BSA) 10 percent, and static Physician Global Assessment (sPGA) score 3. Patients included in the study had inadequate response, inability to tolerate, or contraindication to one conventional systemic agent for the treatment of psoriasis. Patients who were excluded had prior treatment with more than three systemic agents for the management of psoriasis, other clinically significant or major uncontrolled diseases, and/or serious infections, including latent, active, or history of incompletely treated tuberculosis. LIBERATE consisted of two treatment phases: a 16-week randomized, double-blind, PBO-controlled phase and an 88-week APR extension phase for an overall treatment duration of 104 weeks. Patients were randomized (1:1:1) to PBO, APR, or etanercept 50mg once-weekly (ETN). At Week 16, all patients in the PBO and ETN groups switched to APR, and patients in the APR group continued APR. Treatment with APR was maintained from Weeks 16 to 104 (APR extension phase).
At Weeks 16 and 104, the proportion of patients achieving response, defined as the minimal clinically important difference (MCID), was evaluated for the following patient-reported outcomes: 1) Dermatology Life Quality Index (DLQI) MCID defined as an at least 5-point decrease from baseline in patients with baseline DLQI score over 5; 2) pruritus Visual Analog Scale (VAS; 0–100mm) MCID defined as an at least 20 percent decrease from baseline; 3) 36-Item Short Form Health Survey version 2 (SF-36v2) Mental and Physical Component Summary scores (MCS and PCS)–both MCIDs defined as an increase of at least 2.5 points from baseline; and 4) Patient Health Questionnaire-8 (PHQ-8)–MCID defined as achievement of score 4 (no significant depressive symptoms). Safety was assessed based on adverse events (AEs), vital signs, clinical laboratory assessments, and physical examinations. Achievement of MCID on the DLQI at Week 16 and Week 104 was a prespecified exploratory endpoint, whereas achievement of MCID on the pruritus VAS, the MCS and PCS, and the PHQ-8 were post-hoc analyses. All MCID analyses were performed using the modified intent-to-treat (mITT) population, which included all randomized patients who received one dose of study medication and had an evaluation at baseline and at the specified time point. Endpoints were analyzed using descriptive statistics, including proportions of patients achieving each endpoint by treatment group; associated 95-percent confidence intervals (CIs) were calculated. All data were analyzed as observed, with no imputation for missing values. The safety population consisted of all patients who were randomized and received one dose of study medication. Descriptive statistics were used for summaries of treatment-emergent AEs and other safety assessments.
Results: The mITT population consisted of 250 patients (PBO, n=84; APR, n=83; ETN, n=83). Patient demographics and baseline disease characteristics were generally comparable between treatment groups. The proportions of patients achieving the MCID for the MCS were generally similar among the treatment groups at Week 16. At Week 104, MCS response was maintained in PBO/APR patients and was comparable between APR/APR and ETN/APR patients at Week 104. At Week 16, the proportion of patients achieving PCS MCID was lowest in the PBO group. At Week 104, PCS response was comparable between the APR/APR and ETN/APR groups and remained lower in the PBO/APR group.
At Week 16 and Week 104, proportions of patients achieving the MCID for PHQ-8 (i.e., score 4 [no significant depressive symptoms]) were generally similar among the treatment groups; response was maintained at Week 104 in the APR/APR group and in patients who switched at Week 16 from ETN or PBO to APR. During the PBO-controlled period (Weeks 0 to 16), AEs occurring in five percent of patients in any treatment group were diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, headache, and tension headache. During the APR extension phase (Weeks 16–104), AEs that occurred in five percent of patients in any treatment group included those observed during the PBO-controlled period as well as arthralgia, rebound psoriasis, pain in extremity, bronchitis, psoriasis, and sinusitis. Most AEs were mild or moderate in severity, did not increase with prolonged APR exposure, and did not lead to study discontinuation. No clinically meaningful changes were reported in laboratory parameters. No cases of tuberculosis (new or reactivation) were reported during the trial.
Conclusion: In biologic-naive patients with moderate-to-severe psoriasis, improvements in patient-reported outcomes, including QOL and pruritus, were generally maintained with continued APR treatment up to 104 weeks. AEs were consistent with the known safety profile of APR.
Funding/Dislcosures: The authors acknowledge financial support for this study from Celgene Corporation. Joshua Cirulli is an employee of the Celgene Corporation.