Upadacitinib Shows Consistent Safety Profile for Rheumatoid Arthritis

Stanley B. Cohen, MD

Data from 5 pivotal, randomized, double-blind, controlled phase 3 trials assessing upadacitinitib (RINVOQ) in patients with rheumatoid arthritis show the therapy’s safety profile mirrors the reported adverse events in competitor drugs methotrexate and adalimumab.

In a new assessment presented at the Congress of Clinical Rheumatology (CCR) West 2019 Annual Meeting in San Diego, a multi-national team of investigators showed comprehensive safety findings of the oral Janus kinase (JAK) inhibitor across its 5 pivotal phase 3 trials across varied patient populations affected with rheumatoid arthritis.

The findings show the recently-approved AbbVie therapy has safety outcomes comparable to similarly-indicated drugs for arthritis.

Led by Stanley B. Cohen, MD, of the Metroplex Clinical Research Center in Dallas, investigators sought to interpret the overall safety of upadicitinib in patients with moderately to severely active rheumatoid arthritis, based on the phase 3 clinical program database findings.

Their integrated safety analysis included the SELECT trials, which included 3 placebo-controlled studies with exposures up to 14 weeks (SELECT-NEXT, SELECT-BEYOND, SELECT-COMPARE) and a pair of methotrexate-controlled studies with a mean exposure of 36 weeks (SELECT-EARLY, SELECT-MONOTHERAPY). Investigators also used SELECT-COMPARE data to assess for a comparison to adalimumab-controlled patients, with a mean exposure of 42 weeks.

The 5 studies were used to pool phase 3 upadacitinib 15 mg data, with a mean exposure of 53 weeks. Four of the trials provided pooled data for a 30-mg dose of the therapy, with a mean exposure of 59 weeks.

A total of 589 (22%) patients and 382 (32%) patients received upadacitinib 15 mg and 30 mg for ≥72 weeks, respectively. Patients who switched from controlled therapy to the observed therapy were included in the upadacitinib analysis from the start of their therapy initiation; patients in SELECT-COMPARE who switched upadacitinib to adalimumab were included in the latter’s safety dataset.

Investigators had 4020.1 patient-years of upadacitinib exposure with either dose regimen. Four-fifths of all observed patients were female, with a median time of 3.7-6.4 years to rheumatoid arthritis diagnosis. Disease status as per DAS28, as well as cardiovascular risk factors, were common across observed groups.

Overall serious adverse event (SAE) and adverse event (AE) rates leading to discontinuation of 15 mg upadacitinib were comparable to adalimumab, yet higher than methotrexate. The rates of SAEs and AEs leading to discontinuation of 30 mg upadacitinib were higher than that of the 15 mg rate.

The most commonly reported AEs included upper respiratory tract infection, nasopharyngitis, and urinary tract infections for the 15 mg treatment group; for the 30 mg group, the most commonly reported AEs were upper respiratory tract infection and nasopharyngitis.

The rates of death—of which there were 35 total—were comparable across all treatment groups. Among all causes of death, cardiovascular events (n = 15) were the most common, including myocardial infarction. All patients experience a major adverse cardiovascular event during the trial had at least 1 cardiovascular risk factor identified at baseline.

A dose-dependent increase was observed for cardiovascular risk markers including LDL-C and HDL-C levels in patients on upadacitinib; this was consistent with other observed JAK inhibitor therapies.

Rates of reported herpes zoster (HZ) was greater with both doses of upadacitinib than that of methotrexate or adalimumab. Serious infection events (SIEs) were similar between 15 mg treatment and adalimumab, yet greater than that of placebo or methotrexate. For 30 mg therapy, the SIEs rate was greater than that of methotrexate.

Cohen and colleagues concluded the findings established a comprehensive safety profile which reflected the known benefits and risks of upadacitinib in treated patients with rheumatoid arthritis.

“The overall safety profile of upadacitinib reveals both similarities and differences when compared to methotrexate or adalimumab,” they wrote.

The study, “Safety Profile of Upadacitinib in Rheumatoid Arthritis: Integreated Analyses From the SELECT Phase 3 Clinical Program,” was presented at CCR West 2019.