Apremilast Versus Placebo in Japanese Patients with Palmoplantar Pustulosis: A 52-Week, Multicentre, Randomised, Placebo-Controlled, Phase 3 Trial

Background: Palmoplantar pustulosis (PPP) is a difficult to treat chronic dermatitis with limited treatment options. We report results from a phase 3 study of apremilast in patients with moderate to severe PPP. Methods: In this randomised, placebo-controlled, double-blind, confirmatory study, Japanese adults with PPP Area and Severity Index (PPPASI) total score ≥12, PPPASI pustules/vesicles severity score ≥2, and inadequate response to topicals were randomly assigned (1:1) to apremilast or placebo for 16 weeks, followed by an active treatment phase where all patients received apremilast through week 52. The primary endpoint was ≥50% reduction in PPPASI total score (PPPASI-50) at week 16, evaluated in all randomised patients. Safety outcomes were assessed in all patients who received ≥1 dose of study drug. This closed study is registered with ClinicalTrials.gov (NCT05174065). Findings: Between 8 March 2022 and 28 April 2023, 176 patients (141 [80%] women, 35 [20%] men) were randomly assigned to apremilast (n=88 [50%]) or placebo (n=88 [50%]). Mean (SD) PPPASI total score at baseline was 22·1 (8·1) in the apremilast group and 22··0 (8··4) in the placebo group. A significantly greater proportion of patients achieved PPPASI-50 at week 16 with apremilast vs placebo (60 of 88 [68%] vs 31 of 88 [35%]; treatment difference: 32·6% [95% CI: 18·7, 46·5], p<0·0001). Improvements were maintained through Week 52. The most common adverse events (≥10% of patients) during the double-blind phase in patients receiving apremilast were diarrhoea (placebo: n=3 [3%]; apremilast: n=17 [19%]), faeces soft (placebo: n=1 [1%]; apremilast: n=15 [17%]), headache (placebo: n=2 [2%]; apremilast: n=10 [11%]), and nausea (placebo: n=1 [1%]; apremilast: n=10 [11%]). There were no events of depression or fatal adverse events.

Interpretation: In this phase 3 trial, apremilast was effective in Japanese patients with PPP. Adverse events were consistent with the known safety profile of apremilast. Trial Registration: This closed study is registered with ClinicalTrials.gov (NCT05174065). Funding: Amgen, Inc. Declaration of Interest: Tadashi Terui: Maruho – research funding; AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen Pharma, Kyowa Hakko Kirin, LEO Pharma, Mitsubishi Tanabe Pharma, Novartis, Sanofi, and Taiho Pharmaceutical – honoraria for speaking, consultancy, and/or advisory board membership. Yukari Okubo: Eisai, Maruho, Shiseido, and Torii – research grants; AbbVie, Amgen , Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly, Janssen Pharma, Jimro, Kyowa Kirin, LEO Pharma, Maruho, Novartis Pharma, Pfizer, Sanofi, Sun Pharma, Taiho, Tanabe- Mitsubishi, Torii, and UCB – honoraria; AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen Pharma, LEO Pharma, Maruho, Pfizer, Sun Pharma, and UCB – clinical trials Satomi Kobayashi: Kyowa Kirin – research grants; AbbVie, Eli Lilly, Janssen Pharma, Maruho Pharmaceutical, Novartis, and Taiho Pharmaceutical – honoraria; AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen Pharma, Kyowa Kirin, Maruho Pharmaceutical, and Pfizer – clinical trials. Akimichi Morita: AbbVie, Amgen Inc., Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Eisai, Janssen Pharma, Kyowa Hakko Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe, Nichi-Iko, Nippon Kayaku, Novartis, Pfizer, Sun Pharmaceutical Industries, Taiho Pharmaceutical, Torii Pharmaceutical, Ushio, and UCB Pharma – research grants, consulting fees, and/or speaker fees. Shinichi Imafuku: AbbVie, Amgen Inc., Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen Pharma, Kyowa Kirin, LEO Pharma, Maruho, Novartis, Sun Pharma, Taiho Yakuhin, Torii Yakuhin, and UCB – grants and/or personal fees. Yayoi Tada: AbbVie, Amgen Inc., Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly, Janssen Pharma, Jimro, Kaken, Kyowa Kirin, LEO Pharma, Maruho, Meiji Seika Pharma, Novartis, Pfizer, Sun Pharma, Taiho, Tanabe-Mitsubishi, Torii, and UCB – research grants, consulting fees, and/or speaker fees. Masatoshi Abe: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Kyowa Kirin, LEO Pharma, Maruho, Novartis, Otsuka, Sun Pharma, Sanofi, Torii, and UCB – research grants, consulting fees, speaker fees, and/or participated in clinical trials. Bruce Strober: AbbVie, Almirall, Amgen Inc., Arcutis, Arena, Aristea, Boehringer Ingelheim, Bristol Myers Squibb, Connect Biopharma, Dermavant, Dermira, Eli Lilly, Equillium, GlaxoSmithKline, Immunic Therapeutics, Janssen, LEO Pharma, Maruho, Meiji Seika Pharma, Mindera, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi-Genzyme, Sun Pharma, and UCB – consultant (honoraria); AbbVie, Amgen, Eli Lilly, Janssen, Sanofi-Genzyme – speaker; CorEvitas’ Psoriasis Registry – co-scientific director (consulting fee); AbbVie, Cara, CorEvitas’ Psoriasis Registry, Dermavant, Dermira, and Novartis – investigator; Journal of Psoriasis and Psoriatic Arthritis – Editor-in-Chief (honorarium). Melinda Gooderham: AbbVie, Amgen Inc., Akros, Arcutis, Boehringer Ingelheim, Celgene Corporation, Dermira, Dermavant, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin Pharma, LEO Pharma, MedImmune, Merck & Co., Inc., Novartis, Pfizer, Regeneron, Roche Laboratories, Sanofi Genzyme, Takeda Pharmaceuticals USA Inc., UCB, and Bausch/Valeant – honoraria, grants, and/or research funding as a speaker, investigator, advisory board member, data safety monitoring board member, and/or consultant. Wendy Zhang and Hamid Amouzadeh: Amgen Inc. – employees and stockholders. Junichiro Shimauchi, Masafumi Yaguchi, Takeshi Kimura, and Ryuichi Ogawa: Amgen K.K. – employees and stockholders. Masamoto Murakami: AbbVie, ARISTEA Therapeutics, Eisai, Eli Lilly, Kyowa Kirin, and Novartis Pharma – research grants; AbbVie, Amgen Inc., Boehringer Ingelheim, Celgene, Eisai, Eli Lilly, Janssen Pharma, Kyowa Kirin, Maruho, Novartis Pharma, Taiho, and Torii – honoraria; AbbVie, Amgen Inc., Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen Pharma, Maruho, and Novartis Pharma – clinical trials. Ethical Approval: The study protocol was approved by the Institutional Review Board or Independent Ethics Committee before study commencement. The principal investigator and subinvestigators were responsible for conducting the study in full accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines. Patients provided written informed consent before commencement of study procedures.