乌鸦传媒

BOSTON -- A new mechanistic strategy for atopic dermatitis reduced disease activity by as much as 60% within 8 weeks in a preliminary clinical evaluation.

Patients treated with the two highest doses of eblasakimab had 61% reductions in the baseline Eczema Area and Severity Index (EASI). As many as three-fourths of patients had at least a 50% reduction (EASI-50), and at least half of the patients treated with three different doses had at least a 75% response (EASI-75).

Rates of moderate/severe adverse events were similar with the highest dose of the interleukin (IL)-13/IL-4 inhibitor as with placebo, reported Andrew Blauvelt, MD, of the Oregon Medical Research Center in Portland, during the American Academy of Dermatology annual meeting here.

"In this proof-of-concept, early-phase, first-in-human study, nice efficacy was shown, in my view, and that has led to a phase IIb dose-ranging study that's ongoing," he said.

In response to a question from the audience, Blauvelt said the drug's partial inhibition of IL-4 signaling may contribute both to efficacy and to a potentially favorable safety profile.

A second presentation at the meeting showed that the IL-13 inhibitor lebrikizumab led to EASI-75 responses in about half of patients by 16 weeks in two phase III trials of the drug. In both studies, lebrikizumab-treated patients had statistically significant improvement versus in Investigator's Global Assessment (IGA), itch, and EASI-90 response as early as week 4, reported Eric Simpson, MD, of Oregon Health and Science University in Portland.

Targeting IL-13 and IL-4

Both IL-4 and IL-13 have pivotal roles in the pathogenesis of atopic dermatitis and other allergic diseases, Blauvelt noted in his introductory comments. Despite increased and more effective treatment options for atopic dermatitis, some patients still have inadequate responses.

Eblasakimab is a first-in-class molecule with a novel mechanism of action. The drug selectively targets IL-13 receptor (R) α1 and blocks both IL-4 and IL-13 signaling through the type 2 receptor. Selective targeting of the type 2 receptor (sparing type 1) offers the potential to avoid unwanted effects, said Blauvelt.

The initial clinical study of the antibody involved adults with moderate or severe atopic dermatitis of at least 3 years' duration, EASI score ≥16, IGA score ≥3, and at least 10% body surface area (BSA) involvement.

During a dose-escalation study, 24 patients were randomized 1:3 to placebo or to one of three weekly doses of eblasakimab (200-600 mg). Subsequently, an additional 27 patients were randomized 2:1 to the 600-mg dose of eblasakimab or placebo. The primary endpoint was the percent improvement in EASI from baseline to 8 weeks.

The results showed reductions in EASI score by 32% with placebo versus 50% with the 200-mg dose of eblasakimab, 63% with 400 mg, and 61% with 600 mg (P=0.023). Improvement was evident within the first week.

Analysis of the secondary endpoints of EASI-50 and EASI-75 showed 8-week response rates of 38% and 13% with placebo as compared with 71% and 57% with the 400-mg dose of eblasakimab and 77% and 50% with the 600-mg dose (P=0.016 and 0.018 vs placebo). Itch score decreased by 16% with placebo versus 37% with the highest dose of the monoclonal antibody (P=0.032).

Adverse events (AEs) leading to discontinuation occurred more often with placebo. The only serious AE (abdominal pain) occurred in the 400-mg eblasakimab group and was considered unrelated to treatment, said Blauvelt.

With regard to AEs of interest, conjunctivitis occurred in a total of three eblasakimab-treated patients. Blauvelt said conjunctivitis is a recognized risk with dupilumab (Dupixent) and one that developers of "post-dupilumab" drugs are trying to avoid.

Two Phase III Trials

Lebrikizumab also but does so by selectively preventing formation of the IL-13Rα1/IL-4Rα heterodimer signaling complex. The drug produced rapid, dose-dependent efficacy with a favorable safety profile in a of patients with moderate or severe atopic dermatitis, setting the stage for phase III investigation, said Simpson.

The ADvocate1 and ADvocate2 trials enrolled patients with an EASI ≥16, IGA ≥3, BSA ≥10%, disease duration ≥1 year, and no prior exposure to dupilumab or tralokinumab (Adbry). Patients were randomized 2:1 to lebrikizumab or placebo every other week for 16 weeks. The primary endpoints were IGA 0-1 with ≥2 point improvement from baseline and EASI-75, both assessed after 16 weeks.

ADvocate1 enrolled 424 patients and ADvocate2 accrued 429. The two study populations had baseline EASI of about 30, BSA of 46%, and pruritus score of about 7 on a scale of 0-10.

The 16-week results for ADvocate1 showed an IGA response in 43% of the lebrikizumab arm and 12.8% with placebo (P<0.001). EASI-75 response rates were 59.3% vs 16.4%. In ADvocate2, 33.1% of lebrikizumab-treated patients met IGA response criteria versus 10.9% with placebo, and EASI-75 response rates were 50.9% and 16.2% (P<0.001). In both trials, significant differences emerged within the first 4 weeks.

EASI-90, itch score, sleep score, and quality of life all favored lebrikizumab similarly in the two trials.

Treatment-emergent AEs occurred more often in the placebo arms of the two trials, including mild, moderate, and severe cases. Conjunctivitis occurred in about 7% of patients treated with lebrikizumab and was mild or moderate in severity in most cases.

"Lebrikizumab every 2 weeks is efficacious in providing clinically meaningful improvements in the signs and symptoms of atopic dermatitis in adult and adolescent patients with moderate-to-severe AD," said Simpson. "Lebrikizumab demonstrated rapid onset of action. The safety profile was consistent with previous lebrikizumab atopic dermatitis studies."

Patients who met the primary endpoints of the ADvocate1 trial were re-randomized 2:2:1 to two lebrikizumab dosing schedules or placebo and will be followed to 52 weeks.

Lebrikizumab also is being evaluated as treatment for asthma.