A Review of Safety Outcomes from Clinical Trials of Baricitinib in Rheumatology, Dermatology and COVID-19

Abstract

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on adverse events of special interest (AESI) for JAK inhibitors, using integrated safety data sets of clinical trial data, and puts findings into context with the underlying risk in the respective disease populations, using supporting literature. We show that rates of infection with baricitinib generally reflected the inherent risk of the disease populations being treated, with serious infections and herpes zoster being more frequent in rheumatic diseases than in dermatological disorders, and herpes simplex being reported particularly in atopic dermatitis. Similarly, rates of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies were generally within or below the ranges reported for the respective disease populations, thereby reflecting the underlying risk; these events were therefore more frequent in patients with rheumatic diseases than in those with dermatological disorders, the latter of whom generally had low absolute risk. AESI were usually more common in patients with risk factors specific for each event. When a population similar to that of ORAL Surveillance was considered, the incidence rate of MACE with baricitinib was numerically lower than that reported with tofacitinib and similar to that of tumour necrosis factor inhibitors. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Identifying the patterns and likelihoods of AEs that occur during treatment in large groups of patients with different diseases can help the physician and patient better contextualise the benefit-to-risk ratio for the individual patient.

Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications

“…The IR of MACE in the baricitinib clinical data for the at-risk RA subpopulation of ≥ 65 years old with at least one risk factor was 0.70 per 100 PY and much lower for the RA low-risk population, 0.05 per 100 PY. Both fall within the expected IR of MACE in patients with RA reported in real-world settings (0.27–3.2 per 100 PY) [ 28 ]. A retrospective observational study pooling data from disease registries and claims databases, with the French SNDS and Swedish ARTIS data sources contributing the most patients, has investigated the safety of baricitinib compared with TNFi in a matched RA population based on propensity scores for confounding factors.…”

“…For the baricitinib clinical programme in patients with AD, IR for MACE in the at-risk subpopulation (0.25 per 100 PY) lies within the expected rates for the AD patient population reported in real-world settings (IR of 0.15–0.63 per 100 PY), with the low-risk AD baricitinib clinical population having a much lower IR (0.04) [ 28 ]. The IRs for patients with AA in the baricitinib clinical studies (subpopulation at-risk and low-risk, 0.10 and 0 per 100 PY, respectively) are the lowest of those observed in the baricitinib studies, and reflect that the general population of patients with AA do not have an increase in risk of MACE.…”

“…Baricitinib, an oral selective JAK 1/2 inhibitor, is approved for the treatment of adults with moderately-to-severely active RA, moderate-to-severe AD, severe AA, and, in the United States, hospitalised patients with coronavirus disease 2019 (COVID-19). This report complements the recently published cross-indication safety review of baricitinib [ 28 ] by expanding on the safety of baricitinib for adverse events of special interest (AESI) for JAKi in populations with risk factors for these AESI, using integrated clinical trial datasets for the approved systemic inflammatory indications of RA, AD, and AA. These safety events, including MACE, VTE, malignancy, serious infections, and mortality, were investigated for patients aged 65 years or older, or with at least one of eight specified risk factors: history of atherosclerotic cardiovascular disease (ASCVD), hypertension, diabetes mellitus, current smoking, high-density lipoprotein (HDL) cholesterol less than 40 mg/dL, history of malignancy, body mass index (BMI) 30 kg/m 2 or greater, and severe mobility impairment on the EuroQol-5 Dimension (EQ-5D).…”

“…1 ). The IR for AESI in this population were in general lower compared to RA, reflecting different baseline risk [ 28 ]. In this low-risk population, 1 patient (0.1%, IR = 0.04) reported MACE: a female patient of 39 years who had a haemorrhagic stroke due to a ruptured cerebral aneurysm and hence was not related to a thromboembolic process.…”

Evaluation of VTE, MACE, and Serious Infections Among Patients with RA Treated with Baricitinib Compared to TNFi: A Multi-Database Study of Patients in Routine Care Using Disease Registries and Claims Databases

“…There did not appear to be differences between the 4 mg (VTE, MACE, and serious infection IRs of 0.51, 0.54, and 2.62, respectively, per 100 person-years) and 2 mg (VTE, MACE, and serious infection IRs of 0.49, 0.42, and 2.13, respectively, per 100 personyears) doses based on the available information. Observed VTE, MACE, and serious infection IRs in patients treated with baricitinib from the clinical development program and other RA populations from various external sources suggests they are numerically similar although no statistical comparison was conducted [39]. However, results from controlled comparative studies, including observational studies such as B023, suggest that incidence rates of these safety outcomes in patients treated with JAKi, including baricitinib, are elevated compared to similar populations treated with TNFi.…”