Efficacy and Safety of Apremilast for the Treatment of Japanese Patients with Palmoplantar Pustulosis: Results from a Phase 2, Randomized, Placebo-Controlled Study

Abstract

Background: Palmoplantar pustulosis (PPP) is a pruritic, painful, recurrent, and chronic dermatitis with limited therapeutic options.

Objective: To evaluate the efficacy and safety of apremilast for the treatment of Japanese patients with PPP and inadequate response to topical treatment.

Methods: This phase 2, randomized, double-blind, placebo-controlled study enrolled patients with Palmoplantar Pustulosis Area and Severity Index (PPPASI) total score ≥ 12 and moderate or severe pustules/vesicles on the palm or sole (PPPASI pustule/vesicle severity score ≥ 2) at screening and baseline with an inadequate response to topical treatment. Patients were randomized (1:1) to apremilast 30 mg twice daily or placebo for 16 weeks, followed by a 16-week extension phase during which all patients received apremilast. The primary endpoint was achievement of PPPASI-50 response (≥ 50% improvement from baseline in PPPASI). Key secondary endpoints included change from baseline in PPPASI total score, Palmoplantar Pustulosis Severity Index (PPSI), and patient's visual analog scale (VAS) for PPP symptoms (pruritus and discomfort/pain).

Results: A total of 90 patients were randomized (apremilast: 46; placebo: 44). A significantly greater proportion of patients achieved PPPASI-50 at week 16 with apremilast versus placebo (P = 0.0003). Patients receiving apremilast showed greater improvement in PPPASI at week 16 versus placebo (nominal P = 0.0013), as well as PPSI and patient-reported pruritus and discomfort/pain (nominal P ≤ 0.001 for all). Improvements were sustained through week 32 with apremilast treatment. The most common treatment-emergent adverse events included diarrhea, abdominal discomfort, headache, and nausea.

Conclusions: Apremilast treatment demonstrated greater improvements in disease severity and patient-reported symptoms versus placebo at week 16 in Japanese patients with PPP with sustained improvements through week 32. No new safety signals were observed.

Clinicaltrials: GOV: NCT04057937.

Fig. 1

Proportion of patients with PPPASI-50, PPPASI-75, and PPPASI-90 responses at Week 16. Intent-to-treat population. *Two-sided P-value is based on chi-square test. Missing data were imputed by nonresponder imputation. ^†Two-sided P-value (nominal) based on Cochran–Mantel–Haenszel test adjusting for baseline PPPASI score range and baseline focal infection status at baseline. BID twice daily, CI confidence interval, PPPASI Palmoplantar Pustulosis Area and Severity Index; PPPASI-50/75/90, ≥50%/75%/90% improvement from baseline in PPPASI total score

Fig. 2

Change from Baseline in PPPASI total score and PPSI score at Week 16 after treatment with apremilast or placebo (ITT population). Error bars represent 95% CI. Intent-to-treat population. Differences are based on MMRM model for the change from baseline, with treatment group, visit, treatment-by-visit interaction, PPPASI total score range, and focal infection status at baseline as fixed effects and the baseline value as a covariate. An unstructured covariance matrix that is homogeneous across treatment groups was used. BID twice daily, CI confidence interval, MMRM mixed-effects model for repeated measures, PPPASI Palmoplantar Pustulosis Area and Severity Index, PPSI Palmoplantar Severity Index.

Fig. 3

PGA response rate (score of 0 or 1 and ≥ 2 grade improvement) and change from Baseline in patient’s VAS for PPP symptoms at Week 16 after treatment with apremilast or placebo (ITT population). Data shown for week 16 are LS mean changes and for week 32 are mean changes from baseline. Error bars represent 95% CI. Intent-to-treat population. For PGA response, missing data were imputed by nonresponder imputation. Differences in patient’s VAS assessments are based on MMRM model for the change from baseline, with treatment group, visit, treatment-by-visit interaction, PPPASI total score range, and focal infection status at baseline as fixed effects and the baseline value as a covariate. An unstructured covariance matrix that is homogeneous across treatment groups was used. For patient’s VAS assessments, LS mean values are shown for week 16, and mean values are shown for week 32. APR apremilast 30 mg twice daily, BID twice daily, CI confidence interval, MMRM mixed-effects model for repeated measures, NRI nonresponder imputation, PBO placebo, PGA Physician Global Assessment, PPPASI Palmoplantar Pustulosis Area and Severity Index, VAS visual analog scale.

Fig. 4

Change from Baseline in DLQI at Week 16 and Week 32 (exploratory endpoint). Error bars represent 95% CIs. Intent-to-treat population. Data are presented as observed. BID twice daily, CI confidence interval, DLQI Dermatology Life Quality Index.