Long-term Safety of Risankizumab From 17 Clinical Trials in Patients With Moderate-to-severe Plaque Psoriasis

K.B. Gordon; M. Lebwohl; K.A. Papp; H. Bachelez; J.J. Wu; R.G. Langley; A. Blauvelt; B. Kaplan; M. Shah; Y. Zhao; R. Sinvhal; K. Reich


The British Journal of Dermatology. 2022;186(3):466-475. 

In This Article

Patients and Methods

Patients and Study Treatment

The long-term safety analysis included all risankizumab data for patients who received at least one risankizumab dose (double-blinded or open-label treatment, dose range 18–180 mg; most patients received 150 mg) in 17 phase I–III trials in patients with moderate-to-severe plaque psoriasis. The database cutoff for the ongoing trials in the long-term analysis set was 25 March 2020. Short-term safety (through week 16) was analysed using integrated data from the placebo-controlled double-blinded period of five of these trials (Table S1; see Supporting Information).

Treatment-emergent adverse events (TEAEs) were defined as events with onset after the first dose of study drug until the end of the placebo-controlled period (i.e. 15 weeks after the dose preceding the week 16 dose) for short-term safety analysis, and as events with onset between the first and last dose of risankizumab plus five risankizumab half-lives (20 weeks) for long-term safety analysis. This difference in monitoring periods was based on recent enhanced understanding of the half-life of risankizumab from phase III pharmacokinetic data.[12]

Patient eligibility criteria for the included trials are provided in Appendix S1 (see Supporting Information). Of note, patients with the following conditions were not excluded: inflammatory bowel disease; suicidal ideation and behaviour; depression; latent tuberculosis (prophylaxis was mandatory only if required for comparator); active, ongoing cardiovascular or cerebrovascular disease (unless severe); successfully treated nonmelanoma skin cancer (NMSC) or carcinoma in situ; or a history of successfully treated malignancy > 5 years prior to enrolment. Patients with a history of HIV, hepatitis C or acute or chronic hepatitis B were excluded from participation in risankizumab clinical trials. Patients previously treated with IL-12/IL-23 inhibitors, IL-17 inhibitors or tumour necrosis factor inhibitors within 6 weeks to 6 months (depending on drug) or other systemic immunomodulators (within 30 days) prior to study start were excluded. Patients previously treated with IL-23 inhibitors at any time were excluded from phase III trials.

Individual studies were conducted in accordance with the International Conference on Harmonisation guidelines, applicable regulations and the principles of the Declaration of Helsinki that were in place at the time the studies were conducted. Studies and study-related documents were approved by independent ethics committees or institutional review boards, and all patients provided written informed consent.

In all studies, participation was terminated for safety reasons if, in the opinion of the sponsor or the investigator, continued exposure to the study medication represented a significant risk. Other reasons for discontinuation included lack of efficacy, patient withdrawal, other medical reasons [e.g. surgery, adverse events (AEs), other diseases or pregnancy] or loss to follow-up.

Integrated Analyses of Safety Outcomes

Safety data were pooled at the individual patient level. Rates of AEs were expressed as exposure-adjusted event rates (EAERs) per 100 patient-years (PY) for the entire treatment period and were coded using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (https://www.meddra.org), versions 22.1 and 20.0 for long- and short-term analysis, respectively.

Short-term safety (up to 16 weeks) was analysed in the integrated data from the double-blinded placebo- or active-comparator-controlled periods of one phase II and four phase III clinical trials. In addition to these five trials, the long-term safety analysis set also included data from two phase I studies, one phase II extension study, one phase IIb/III study, seven phase III studies and a phase II/III extension study, for a total of 17 studies. The majority of patients in both analysis datasets received the standard 150-mg dose of risankizumab.

The analysis populations for short- and long-term safety consist of different sets of patients, and patients included in the long-term analysis set have varying lengths of treatment exposure. Any risankizumab safety events included in the short-term analysis set are also included in the long-term analysis set.

Statistical Analysis

EAERs with 95% exact Poisson confidence intervals (CIs) were calculated using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). For the displays of rates over 6- or 12-month intervals, the total PY of exposure and number of events in each interval were used to calculate the EAER and 95% CI. The standardized mortality ratio of risankizumab-treated patients was calculated as the ratio of observed (treatment-emergent) to expected deaths using mortality data from the World Health Organization (2015) adjusting for country, sex, age and length of risankizumab exposure.[13]