麻豆传媒

An oral Janus kinase 1 (JAK1) inhibitor significantly improved signs and symptoms of atopic dermatitis (AD) versus placebo, and reduced itch versus dupilumab (Dupixent) at the higher of two doses evaluated, a large manufacturer-sponsored trial showed.

After 12 weeks of treatment, almost half patients randomized to the higher dose of abrocitinib had an investigator's global assessment (IGA) score of 0 or 1, as did 36.6% of patients allocated to the lower dose of the JAK inhibitor. That compared with 36.5% of patients treated with dupilumab and 14.0% of placebo-treated patients.

More patients treated with the higher dose of abrocitinib had an Eczema Area and Severity Index 75 (EASI-75) response (75% improvement from baseline) as compared with the other three randomized groups, reported Hernan Valdez, MD, of Pfizer in New York City, and colleagues in the .

"In the trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo on the basis of IGA and EASI-75 responses at weeks 12 and 16," the authors stated. "The 100-mg dose of abrocitinib was not significantly different from dupilumab with respect to the three key secondary endpoints of the trial."

"The 200-mg dose of abrocitinib was superior to dupilumab with respect to itch response at week 2 but not to an EASI-75 response at week 16; no conclusion could be drawn regarding the difference between the 200-mg dose of abrocitinib and dupilumab with respect to an IGA response... . Longer and larger trials are necessary to determine the efficacy and safety of abrocitinib and to compare it with other JAK inhibitors and with biologic agents used for the treatment of atopic dermatitis," they added.

On the strength of this and two other phase III trials, drugmaker Pfizer has , with a decision expected sometime next month.

Abrocitinib is one of several oral JAK inhibitors in clinical evaluation for AD. Targeting JAK1 leads to inhibition of signaling by interleukin (IL)-4, IL-13, and other cytokines involved in the pathogenesis of AD, the authors noted. Data from head-to-head trials of JAK inhibitors for AD are lacking.

A by the National Eczema Association emphasized the lack of new FDA-approved therapies for AD, aside from crisaborole (Eucrisa) in 2016 and dupilumab in 2017. The review characterized JAK inhibitors as the "biggest eczema development in years." The author of a review in the cited JAK inhibitors as key drivers of impending "major breakthroughs in the treatment of atopic dermatitis."

The positive vibe surrounding JAK inhibitors for AD could be tempered somewhat by results of a recent FDA-mandated postmarketing safety study of tofacitinib (Xeljanz), which has multiple approvals for arthritis, as well as ulcerative colitis. The data showed a significantly higher rate of malignancies in patients treated with the JAK inhibitor as compared with a tumor necrosis factor inhibitor. Additionally, tofacitinib was associated with a numerically higher rate of major adverse cardiovascular events (MACEs).

Valdez and colleagues reported findings from a phase III randomized trial involving 838 patients with moderate or severe AD (baseline IGA score 3 or 4, EASI score of 30 to 32). The patients were randomized 2:2:2:1 to abrocitinib 100 mg or 200 mg, dupilumab, or placebo. All patients continued existing background topical treatment.

The trial had two primary endpoints: IGA response at week 12 and EASI-75 response at week 12. Both endpoints were compared versus placebo. Secondary analyses included comparisons of itch response at week 2 versus placebo and dupilumab and IGA and EASI-75 responses versus placebo at week 16.

Significantly more patients treated with either dose of abrocitinib had IGA responses at week 12 as compared with the placebo group (P<0.001). The proportion of patients with an EASI-75 response at 12 weeks was 70.3% with abrocitinib 200 mg, 58.7% for abrocitinib 100 mg, 58.1% for dupilumab, and 27.1% for placebo. Both abrocitinib groups did significantly better versus placebo (P<0.001).

The proportion of patients with itch response at week 2 was 49.1% with the higher dose of abrocitinib, 31.8% with the lower dose, 26.4% with dupilumab, and 13.8% with placebo. Both abrocitinib groups were superior to placebo (P<0.001), and the 200-mg abrocitinib group was superior to dupilumab (P<0.001). IGA and EASI-75 response rates at 16 weeks were significantly higher in both abrocitinib groups versus placebo (P<0.001).

No deaths, MACEs, or thromboembolic events occurred during the study. Two malignancies occurred, one each in the abrocitinib 200-mg and dupilumab arms. Adverse events (AEs) occurred more often with 200-mg abrocitinib as compared with the other three groups (61.9% vs 50.0% to 53.4%). The most commonly reported AE with the higher dose of abrocitinib was nausea (11.1%). No other AE occurred in as many as 10% of patients in any group.

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