Upadacitinib provides robust, long-term control of moderate-to-severe AD

Follow-up data from two replicate ongoing phase III trials – Measure Up 1 and Measure Up 2 – demonstrated favourable longer-term benefit-risk profile of upadacitinib in adolescents and adults with moderate-to-severe atopic dermatitis (AD).

“There remains an unmet need for efficacious and well-tolerated oral medications that provide rapid, sustained itch relief and skin clearance, and improve quality of life (QoL) for patients with moderate-to-severe AD,” ­said the researchers.

“Because AD is a chronic disease, [we evaluated] the long-term benefit-risk profile of upadacitinib as monotherapy … in the ongoing blinded extension period of [the Measure Up studies],” said the researchers. “[We found that] both upadacitinib doses maintained efficacy responses achieved at week 16 through week 52 for several measures of AD disease activity, patient-reported itch, and patient-reported QoL.”

At week 52, the majority of upadacitinib recipients achieved EASI-75*, both in Measure Up 1 (82 percent [15 mg] and 85 percent [30 mg]) and Measure Up 2 (79 percent and 84 percent, respectively). [JAMA Dermatol 2022;158:404-413]

More than half of upadacitinib 15-mg recipients achieved vIGA-AD** scores of 0/1 (clear/almost clear) with ≥2 grades of improvement (59 percent and 53 percent for Measure Up 1 and 2, respectively). Up to two-thirds of those on upadacitinib 30 mg were able to achieve this endpoint (62 percent and 65 percent, respectively).

Collectively, WP-NRS*** improvement of ≥4 was achieved by 64 percent of upadacitinib-treated patients receiving the 15-mg dose and 70 percent of those on the 30-mg dose.

“[The] improvements in EASI and WP-NRS occurred rapidly (within 1 week) and continued to increase,” the researchers noted.

Among placebo recipients rerandomized to the study drug, response rates through week 52 were similar to those who were initially given upadacitinib.

 

Better QoL outcomes, favourable safety

There were also meaningful improvements in several patient-reported outcome assessments, including DLQI, HADS, and ADerm-IS^#. “These improvements occurred at the earliest weekly timepoint at which they were assessed, with improvements at week 16 maintained through week 52,” they said.

Overall, the rate of discontinuation due to adverse events (AEs) was low but somewhat higher with upadacitinib 30 vs 15 mg (7 percent vs 4 percent). Nonetheless, events were mostly mild to moderate and rarely led to treatment withdrawal. The most common serious infections were pneumonia (Measure Up 1) and eczema herpeticum (Measure Up 2).

Collectively, upadacitinib 30 mg was associated with higher EAERs^## of serious infection (3.6/100 patient years [PYs] vs 2.2/100 PYs) and herpes zoster (HZ; 5.4/100 PYs vs 3.6/100 PYs) than the 15-mg dose. Most HZ events were nonserious, with only one event leading to treatment discontinuation.

Two cases of tuberculosis were reported with upadacitinib use (one with each dose). “[B]oth were serious, deemed possibly related to study drug, and led to treatment withdrawal,” said the researchers.

 

Higher dose, greater benefit?

The combined cohorts comprised 1,609 patients (mean age 33.8 years, 55 percent male) who were randomized 1:1:1 to receive once-daily oral upadacitinib 15 or 30 mg or placebo. After the 16-week double-blind phase, patients initially on upadacitinib carried on with their assigned treatment, while those on placebo were rerandomized 1:1 to either upadacitinib dose.

Despite the high levels of efficacy with upadacitinib 15 mg, the 30-mg dose delivered greater relative benefit in both trials. “Patients on upadacitinib 30 mg consistently reached numerically greater response rates and higher degrees of improvement than did patients on upadacitinib 15 mg for all outcome measures assessed through week 52,” said the researchers.

“The numerically better outcomes with upadacitinib 30 mg through week 52 are more apparent when using the more stringent thresholds of disease activity (ie, vIGA-AD 0 [37 percent], EASI-90* [72 percent], and EASI-100* [36 percent]),” they continued.

“Altogether, while longer-term treatment of moderate-to-severe AD with upadacitinib (both 15 and 30 mg) has a favourable benefit-risk profile, upadacitinib 30 mg may provide added benefit for patients with higher disease burdens that may require more rapid or more complete response to treatment,” said the researchers.

Patients in both trials will be followed through 260 weeks to further elucidate the longer term benefit of upadacitinib for AD.