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 × 10 3 /mm 3 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. Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00618-3.

Abrocitinib: First Approval

“…Abrocitinib is generally well tolerated in patients with AD, based on pooled data from across four ( n = 1,540) [ 27 ] or five ( n = 1,825) [ 3 – 5 ] placebo-controlled trials, from placebo-controlled studies plus JADE REGIMEN (open-label phase) and JADE EXTEND ( n = 2,856) [ 27 ] and from all patients treated with abrocitinib in AD clinical studies, including JADE EXTEND ( n = 3,128) [ 3 – 5 ].…”

“…Confirmed platelet counts < 50 × 10 3 /mm 3 and absolute lymphocyte counts (ALC) < 0.5 × 10 3 /mm 3 were uncommon with abrocitinib 200 or 100 mg/day in the largest pooled analysis of placebo-controlled trials (incidence ≤ 0.3% with either dosage vs 0% with placebo) and among all patients who received abrocitinib 200 or 100 mg/day in clinical trials, including JADE EXTEND (≤ 0.3% with either dosage; quantitative data for proportion of patients with platelet counts < 50 × 10 3 /mm 3 in the 100 mg/day group were not reported) [ 3 – 5 ]. Malignancies have occurred with abrocitinib in clinical studies [ 27 ], although data are not sufficient to determine a relationship between malignancy development and abrocitinib exposure [ 3 – 5 ].…”

Once-Daily Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis in Adults and Adolescents Aged 12 Years and Over: A Short Review of Current Clinical Perspectives

“…An integrated safety analysis study done by Simpson et al found that abrocitinib has a long-term safe profile, being tolerated by moderate-to-severe AD patients that are selected for this type of treatment (both adults and adolescents); the most frequent dose-related and drug-related reported side effects ( Table 3 ) were mild, non-lethal ones, more frequently located at the respiratory and/or gastrointestinal level, such as: headaches, dizziness, nasopharyngitis, symptoms of upper respiratory tract infection, epigastric pain, nausea, vomiting, creatine phosphokinase increase (CK increase without rhabdomyolysis), folliculitis and acne, all with mild or moderate intensity; 8 , 37 , 38 herpes zoster infection was found occurring with a higher frequency in patients receiving 200 mg of abrocitinib in daily oral doses. These adverse effects were self-limited and treatment rarely required interruption or even permanent discontinuation.…”

“…Severe adverse events were also reported, which were considered treatment-related: eczema herpeticum, herpangina and pneumonia (in 100 mg abrocitinib receiving patients), acute pancreatitis, chronic inflammatory bowel disease; in 200 mg abrocitinib receiving patients lowered platelet counts were registered, some patients even suffering from thrombocytopenia. 8 , 9 , 13 , 37 …”

An integrated analysis of herpes virus infections from eight randomized clinical studies of baricitinib in adults with moderate‐to‐severe atopic dermatitis

“…11 A previous history of herpes simplex has also been established as a risk factor with another oral JAK inhibitor. 21 AD is a recognized risk factor for developing an event of HZ and associated with increased hospitalization. 1,22 In this study, TE-HZ occurred less frequently with 4-mg than 2-mg BARI in the PC and extended datasets, indicating no dose-dependent impact of BARI treatment, and no events were reported for 4mg during the PC period making it a very rare event over the first 16 weeks of treatment.…”