Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program

Abstract

Background: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA).

Objective: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA.

Methods: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported.

Results: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events.

Conclusions: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available).

Trial registries: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

Fig. 1

Schematic of the A placebo-controlled pool and B the all-exposure pool. BL baseline

Fig. 2

IRs per 100 PY for adverse events of special interest (a–i). IRs are exposure adjusted and expressed as the number of patients with events per 100 PY. IR incidence rate, MACE major adverse cardiovascular events, NMSC nonmelanoma skin cancer, PY patient-years, VTE venous thromboembolic events. Study size–adjusted IRs are per 100 PY and are shown with mid-p gamma CIs. Ritlecitinib all 30 mg includes patients who received ritlecitinib 30 mg QD with or without an initial 4-week 200-mg QD loading dose. Ritlecitinib all 50 mg and ritlecitinib 50 mg includes patients who received ritlecitinib 50 mg QD with or without an initial 4-week 200-mg QD loading dose from the placebo-controlled and all-exposure pools, respectively. ^aAdjudicated safety events. ^bIRs shown for breast cancer in female patients. ^cMACE was defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ^dVTE was defined as events of deep vein thrombosis and pulmonary embolism

Fig. 3

Select laboratory parameters over time. HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, LLN lower limit of normal, ULN upper limit of normal