Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program

Abstract

Background: Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy.

Objective: The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study.

Methods: Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported.

Results: Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19.

Conclusion: Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD.

Trial registries: ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822.

Conflict of interest statement

E. L. Simpson reports grants from Pfizer Inc., Eli Lilly, Kyowa Kirin, LEO Pharma, Merck, and Regeneron and personal fees from Pfizer Inc., Bausch Health (Valeant), Dermira, Eli Lilly, Galderma, LEO Pharma, Menlo Therapeutics, Novartis, Regeneron, and Sanofi Genzyme. J. I. Silverberg is an investigator for AbbVie, Celgene, Eli Lilly, GSK, Kiniksa, LEO Pharma, Menlo Therapeutics, Realm Therapeutics, Regeneron, Roche, and Sanofi; a consultant for Pfizer Inc., AbbVie, Anacor, AnaptysBio, Arena Pharmaceuticals, Asana Biosciences, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Glenmark, Incyte, Kiniksa, LEO Pharma, MedImmune, Menlo Therapeutics, Novartis, Realm Therapeutics, Regeneron, and Sanofi; a speaker for Regeneron and Sanofi; and is on advisory boards for Pfizer Inc., Dermira, LEO Pharma, and Menlo Therapeutics. A. Nosbaum is an investigator for AbbVie, Eli Lilly, Incyte, LEO Pharma, Novartis, and Sanofi; a consultant for Pfizer Inc., AbbVie, Eli Lilly, Galderma, LEO Pharma, Novartis, and Sanofi; a speaker for AbbVie, Regeneron, and Sanofi; and is on advisory boards for Pfizer Inc., AbbVie, LEO Pharma, and Sanofi. K. L. Winthrop reports research grants from Bristol Myers Squibb and consultant honorarium from Pfizer, Eli Lilly, Bristol Myers Squibb, UCB, AbbVie, Gilead, Roche, Novartis, Regeneron, and Sanofi. E. Guttman-Yassky is an advisory board member for Celgene, Dermira, Galderma, Glenmark, Medimmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, and Asana Biosciences (honorarium); consultant for AbbVie, Anacor, Celgene, Dermira, Galderma, Glenmark, LEO Pharma, Medimmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, Mitsubishi Tanabe, Eli Lilly, Asana Biosciences, Kiowa Kirin, and Almirall (honorarium); and investigator for Celgene, LEO Pharma, Medimmune, Regeneron, and Eli Lilly (grants to institution). K. M. Hoffmeister has received honoraria as consultant from Pfizer. A. Egeberg has received research funding from Pfizer, Eli Lilly, Novartis, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the Simon Spies Foundation, and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, LEO Pharma, Galápagos NV, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly and Company, Novartis, Galderma, Dermavant, UCB, Mylan, Bristol Myers Squibb, and Janssen Pharmaceuticals. H. Valdez, M. Zhang, S. A. Farooqui, W. Romero, A. J. Thorpe, R. Rojo, and S. Johnson are employees of and shareholders in Pfizer.

© 2021. The Author(s).

Figures

Fig. 1

Schematic of a placebo-controlled cohort and b all-abrocitinib cohort

Fig. 2

Clinical safety data from baseline to week 16 for a platelets, b absolute lymphocyte count, c absolute neutrophil count, and d hemoglobin. IQR interquartile range, Q quarter. Boxes span the IQR; stars represent the median value; whiskers delineate the maximum and minimum values (maximum = Q3 + 1.5 × IQR; minimum = Q1 − 1.5 × IQR); circles represent outliers

Fig. 2

Clinical safety data from baseline to week 16 for a platelets, b absolute lymphocyte count, c absolute neutrophil count, and d hemoglobin. IQR interquartile range, Q quarter. Boxes span the IQR; stars represent the median value; whiskers delineate the maximum and minimum values (maximum = Q3 + 1.5 × IQR; minimum = Q1 − 1.5 × IQR); circles represent outliers

Fig. 3

Mean percent change from baseline in a LDL-C and b LDL/HDL ratio by visit in the placebo-controlled cohort. CI confidence interval, HDL high-density lipoprotein, LDL low-density lipoprotein, LDL-C low-density lipoprotein cholesterol. Error bars represent standard error

Fig. 4

Line plot of median (Q1, Q3) creatinine kinase (U/L) data by visit in the placebo-controlled cohort. Q quarter. Error bars represent interquartile range