麻豆传媒

SAN DIEGO -- Patients with moderate or severe atopic dermatitis (AD) had as much as 74% improvement in disease status with the oral Janus kinase (JAK) inhibitor upadacitinib, a randomized trial showed.

After 16 weeks, patients randomized to one of three doses of upadacitinib had a mean improvement of 39.4% to 74.4% in the Eczema Area and Severity Index (EASI), as compared with 23% in the placebo group. Half of the patients had 90% improvement in the index (EASI 90) after 16 weeks. The same proportion met the criteria for almost/completely clear by investigator global assessment criteria (IGA 0/1).

Across the range of doses tested, upadacitinib had a favorable safety profile, Emma Guttman-Yassky, MD, of Mount Sinai Health System in New York City, reported here at the meeting.

"Upadacitinib met all primary and secondary efficacy endpoints in atopic dermatitis. Dose-dependent, rapid, and sustained significant improvements were seen in all dose regimens. No herpes zoster, malignancies, deaths, or cases of pulmonary embolism or deep vein thrombosis were reported."

Results of a separate study, also reported by Guttman-Yassky, showed that 50-60% of patients with moderate/severe AD attained 50% clearance (EASI 50) by 16 weeks with the JAK inhibitor baricitinib plus topical corticosteroids. The magnitude of benefit was similar in patients with moderate or severe AD at baseline.

Prednisone remains the only FDA-approved oral systemic therapy for AD. Improved understanding of the etiology and pathogenesis of AD stimulated interest in targeted therapies, and early studies with JAK inhibitors produced encouraging results.

Upadacitinib is a once-daily, oral JAK1-selective inhibitor under evaluation for several inflammatory diseases, Guttman-Yassky noted. The FDA recently granted breakthrough therapy status for the drug.

Investigators in the multicenter phase II randomized trial compared three different doses of upadacitinib versus placebo. A total of 167 patients with moderate to severe AD received placebo or upadacitinib at a dose of 7.5, 15, or 30 mg/day.

The patients had a mean age of about 40, baseline EASI score of 28-32.6, and mean affected body surface area of 42-51%. One fourth to one half of patients in each group had severe AD, defined by an IGA score of 4.

The trial had a primary endpoint of improvement in baseline EASI score after 16 weeks. By 4 weeks all three upadacitinib groups had at least 50% improvement, and 16-week results showed a mean improvement of 39.4%, 61.7%, and 74.4% with the lowest to highest doses of upadacitinib. The placebo group had mean improvement of 23%. Maximal improvement in all three upadacitinib groups occurred during weeks 8 to 12, including a high of 82.8% at 8 weeks in the 30-mg group.

A review of secondary endpoints showed that 83.3% of patients in the 30-mg upadacitinib arm met EASI 50 criteria at week 16; 69.0% achieved EASI 75; and 50% achieved EASI 90. Corresponding scores for the placebo group were 22.0%, 9.8%, and 2.4%.

Significantly more patients in all three groups assigned to upadacitinib achieved EASI 50, EASI 75, and EASI 90 compared with placebo (P<0.05 to P<0.001). The same was true for mean improvement in pruritus at 16 weeks (40-69%) as compared with placebo (10%, P<0.05 to P<0.001).

Adverse events, serious adverse events, and severe adverse events occurred in a similar proportion of placebo- and upadacitinib-treated patients. Rates of discontinuation because of adverse events were 5.0% with placebo and 2.4-9.5% with upadacitinib. The most common adverse events in all groups (including placebo) were upper respiratory tract infection, worsening of AD, and acne.

With regard to treatment-emergent adverse events of special interest, infection was the most common, occurring in 20% of placebo patients and 41-52% of the upadacitinib groups. Severe infections occurred in a total of three upadacitinib-treated patients. Creatine phosphokinase elevation occurred in seven upadacitinib patients and one placebo patient.

"The emerging positive benefit/risk profile observed for upadacitinib in atopic dermatitis supports proceeding with phase III trials," Guttman-Yassky concluded.

The baricitinib study involved 124 patients with moderate/severe AD, associated with a median EASI score of about 20, median Scoring AD (SCORAD) score of about 55, and median Patient Oriented Eczema Measure (POEM) score of 17-20.

Patients were randomized 4:3:3 to placebo or to baricitinib at 2 or 4 mg/day. All patients began treatment with a 4-week run-in of topical triamcinolone, and patients could continue the topical steroid during randomized therapy, at investigator discretion.

As , 57% and 61% of patients allocated to baricitinib achieved EASI 50 status by week 16. The reduction in EASI score from baseline to 16 weeks was 40% with placebo and the topical steroid, and about 65% in both the baricitinib groups (P<0.001).

Improvement in SCORAD averaged 39% and 47% with baricitinib versus 16% with placebo. In the subgroup of patients with severe AD (EASI >21), improvement with baricitinib averaged about 45% with baricitinib and 12% with placebo.

At the 16-week landmark analysis, patients in both baricitinib groups had significantly greater improvement in POEM score compared with placebo (P<0.01, P<0.001), said Guttman-Yassky. Significantly more improvement in POEM scores was observed at all time points in the baricitinib groups (P<0.05 to P<0.001).