Efficacy and safety of apremilast in systemic- and biologic-naive patients with moderate plaque psoriasis (52-week results of the UNVEIL study)

Efficacy and safety of apremilast in systemic- and biologic-naive patients with moderate plaque psoriasis (52-week results of the UNVEIL study)

Presenters: Strober B¹, Forman S², Bagel J³, Lebwohl M⁴, Stein Gold L⁵, Jackson JM⁶, Goncalves J⁷, Levi E⁷, Callis Duffin K⁸

Affiliations: ¹University of Connecticut, Farmington, CT, and Probity Medical Research, Waterloo, ON, Canada; ²Forward Clinical Trials, Tampa, FL; ³Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; ⁴Icahn School of Medicine at Mount Sinai, New York, NY; ⁵Henry Ford Health System, West Bloomfield, MI; ⁶University of Louisville, Forefront Dermatology, Louisville, KY; ⁷Celgene Corporation, Summit, NJ; ⁸University of Utah, Salt Lake City, UT

Background/Objective: Patients with moderate plaque psoriasis (i.e., 5–10% psoriasis-involved Body Surface Area [BSA]) often receive no treatment or are undertreated with topical monotherapy. Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has been shown to be effective and has demonstrated acceptable tolerability in patients with moderate-to-severe psoriasis (BSA 10%) in the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) Phase III clinical trial program. Evaluating Apremilast in a Phase IV Trial of Efficacy and Safety in Patients With Moderate Plaque Psoriasis (UNVEIL) (ClinicalTrials.gov: NCT02425826) is the first prospective randomized, placebo (PBO)-controlled trial to demonstrate the clinical efficacy and safety of an oral systemic treatment (apremilast) in systemic- and biologic-naive patients with moderate plaque psoriasis. Apremilast 30mg twice-daily (APR) was clinically effective and well tolerated during the 16-week, double-blind, PBO-controlled phase. The efficacy and safety results of the open-label APR treatment phase up to Week 52 are presented.

Methods: UNVEIL is a Phase IV, multicenter, randomized, PBO-controlled, double-blind study. Men and women at least 18 years of age with chronic plaque psoriasis for six months before screening were included in the study. Subjects had moderate plaque psoriasis at screening and baseline as defined by BSA of 5 to 10 percent and static Physician’s Global Assessment (sPGA) of 3 (moderate) based on a scale ranging from 0 (clear) to 5 (very severe). Included subjects had no prior exposure to systemic or biologic treatments for psoriasis, psoriatic arthritis, or any other condition that could affect the assessment of psoriasis. Potential subjects with an inflammatory or dermatologic condition, including forms of psoriasis other than plaque psoriasis, were excluded. Persons using topical therapy within two weeks or phototherapy within four weeks of randomization were also excluded. Patients were randomized (2:1) to receive APR or PBO during Weeks 0 to 16; patients in the PBO group were switched to APR at Week 16. All patients continued taking APR through Week 52.

The primary efficacy endpoint was the mean percentage change from baseline at Week 16 in PGAxBSA, which represents the product of sPGA and BSA scores. Overall BSA affected by psoriasis is estimated based on the patient’s palm area, which equates to approximately one percent of total BSA. For the 6-point sPGA for plaques in all involved areas, the severity of erythema, scaling, and plaque elevation were each scored; scores were averaged and rounded to the nearest whole number. The secondary efficacy endpoint was the proportions of patients achieving a 75-percent reduction from baseline in PGAxBSA score (PGAxBSA-75) and the sPGA response, defined as a score of 0 (clear) or 1 (almost clear). Quality of life (QOL) was assessed with the Dermatology Life Quality Index (DLQI). Safety was evaluated based on adverse events (AEs), vital signs, clinical laboratory testing, and complete physical examinations. Efficacy and QOL assessments were conducted for the intent-to-treat (ITT) population, which included all randomized patients; safety assessments were conducted in all randomized patients who received one dose of study medication. Mean percentage change from baseline in PGAxBSA and change from baseline in DLQI total score at Week 16 were compared between APR and PBO using a two-sided analysis of covariance model (ANOVA) with treatment and site as factors and baseline value as covariate. PGAxBSA-75 and sPGA responses at Week 16 were evaluated with two-sided Cochran-Mantel-Haenszel tests stratified by site. Efficacy and QOL parameters at Week 52 were evaluated descriptively. Week 16 and Week 52 APR/APR analyses were performed with the ITT population. Week 52 PBO/APR analyses were performed with the modified ITT population (all patients who entered the APR extension phase). The last-observation-carried-forward methodology was used to impute missing values. Safety assessments were summarized using frequencies and percentages.

Results: A total of 221 patients were randomized to study treatment and constitute the ITT population; 185 patients (84%) completed the PBO-controlled phase (Weeks 0–16) and 136/185 patients (74%) completed the APR treatment phase (Weeks 16–52). Demographics and baseline disease characteristics were generally similar between treatment groups. At baseline, mean DLQI total score was comparable between treatment groups, and the mean pruritus Visual Analog Scale (VAS) score was slightly higher in the PBO group. At Week 16, significantly greater improvement in PGAxBSA occurred in patients receiving APR (-48.1%) versus PBO (-10.2%). At Week 52, improvement was maintained in the APR/APR group and emerged in the PBO/APR group after switching to APR. Significantly more patients treated with APR achieved PGAxBSA-75 response at Week 16 (35.4%) versus PBO (12.3%). PGAxBSA-75 response was maintained in the open-label APR treatment phase. Significantly more patients treated with APR achieved an sPGA score of 0 or 1 at Week 16 (30.4%) versus PBO (9.6%). Long-term sPGA response was maintained with APR treatment in the open-label treatment phase. Improvement in DLQI was significantly greater with APR (-4.8) than PBO (-2.4) at Week 16. DLQI improvement was maintained in patients continuing on APR for up to 52 weeks and developed after patients were switched from PBO to APR. Most AEs were mild or moderate. The most common AEs (reported in 5% of patients in either treatment group during the PBO-controlled period) included diarrhea, headache, nausea, upper respiratory tract infection, decreased appetite, and vomiting.

Conclusion: APR was clinically effective in systemic- and biologic-naive patients with moderate plaque psoriasis (BSA of 5–10%). APR significantly improved PGAxBSA score, PGAxBSA-75 response rate, sPGA 0 or 1 response rate, and DLQI total score at Week 16 compared with PBO. Clinical responses were maintained with continued APR treatment through Week 52 and emerged in patients who switched from PBO to APR at Week 16. The incidence of AEs, based on EAIR per 100 patient-years, did not increase with longer exposure to APR. Safety and tolerability were consistent with previous studies; no new safety or tolerability issues were observed up to 52 weeks.

Funding/Disclosures: The authors acknowledge financial support for this study from Celgene Corporation. Bruce Strober receives honoraria as a consultant, payments (to the University of Connecticut) as an investigator, and is an advisory board member of Celgene Corporation. Seth Forman receives research support from the Celgene Corporation. Jerry Bagel is an advisory board member, speaker, consultant, and/or receives research support from the Celgene Corporation. Mark Lebwohl is an investigator and/or consultant for the Celgene Corporation. J. Mark Jackson receives research, honoraria, consulting, and/or other support from Celgene Corporation. Joana Goncalves and Eugenia Levi are employees of the Celgene Corporation. Kristina Callis Duffin is a consultant, steering committee member, advisory board member, has received grants, and/or has received honoraria from the Celgene Corporation.