麻豆传媒

WASHINGTON -- An investigational topical phosphodiesterase 4 (PDE4) inhibitor led to statistically and clinically significant improvement in atopic dermatitis with a rapid onset of effect, according to two randomized phase III trials.

About a third of patients achieved skin clearance or near clearance plus at least a two-point improvement in global assessment of disease severity after 29 days of treatment with crisaborole. That compared with about 20% of patients randomized to vehicle control. About half of patients treated with crisaborole achieved clearance or near clearance irrespective of global assessment score, versus 30% to 40% of patients randomized to vehicle.

The novel agent proved safe and effective in patients as young as 2 years, , of the University of Texas Health Science Center in Houston, reported here at the American Academy of Dermatology meeting.

"Crisaborole demonstrated early relief in pruritus and improvement in the severity of all signs of atopic dermatitis," Hebert said. "If approved, crisaborole represents a new, promising, safe and effective treatment for reducing the severity of signs and symptoms of mild-to-moderate atopic dermatitis in patients 2 years of age and older."

In a second presentation at the meeting, a monoclonal antibody targeting interleukin (IL)-31 and the itch-scratch cycle resulted in significant reductions in pruritus, and improvement in dermatitis signs and symptoms, as well as sleep quality in a phase II trial of patients with atopic dermatitis inadequately controlled by topical therapy.

Boron Derivative

Crisaborole is a boron derivative that inhibits 3'-5'-cyclic AMP-dependent PDE4 to effect anti-inflammatory activity. Hebert summarized results of two trials (AD-301 and AD-302) involving patients ≥2 with a clinical diagnosis of mild or moderate atopic dermatitis (investigators's static global assessment, ISGA, 2 or 3). In both trials, the patients were randomized 2:1 to crisaborole or vehicle, applied twice daily for 28 days.

The primary endpoint was the proportion of patients achieving ISGA 0 (clear) or 1 (almost clear) in association with at least a two-point improvement in the scale at day 29. Data analysis included 759 patients in AD-301 and 763 in AD-302.

In AD-301 32.8% of patients met the primary endpoint compared with 25.4% of patients in the control group (P=0.038). In AD-302 the treatment success rates were 31.4% with crisaborole and 18.0% with vehicle (P<0.001).When the two-point improvement in ISGA was excluded, treatment success rates (ISGA 0 or 1) were 51.7% with crisaborole-treated and 40.6% with vehicle in AD-301 (P=0.005) and 48.5% versus 29.7% in AD-302 (P<0.001).

In both trials, patients treated with crisaborole reached the primary endpoint significantly faster (P<0.001).

A predefined pooled analysis of change in the severity of atopic dermatitis signs showed a significant advantage for crisaborole with respect to erythema (-40% vs -20%, P<0.001), exudation (-65% vs -52%, P<0.001), excoriation (-52% vs -34%, P<0.001), induration/papulation (-37% vs -29%, P=0.002), and lichenification (-42% vs -29%, P<0.001).

Significantly more patients treated with crisaborole had improvement in pruritus at days 8 through 29 (P=0.002 to P<001). Median time to improvement in pruritus was 1.37 days with crisaborole and 1.73 days with vehicle (P<0.001).

Adverse events were generally mild, and no serious adverse events occurred with crisaborole or vehicle. The cumulative discontinuation rate for adverse events in the two trials was 1.2% in the crisaborole and vehicle groups.

Monoclonal Antibody

The trial of the monoclonal antibody nemolizumab (formerly CIM331) involved patients whose atopic dermatitis was inadequately controlled by topical therapy. Five groups of approximately 50 patients each were treated for 12 weeks with placebo or one of four different doses/schedules of the anti-IL-31 antibody. The primary endpoint was change in a pruritus visual analog scale (VAS) at 12 weeks, said , of Oregon Health and Science University in Portland.

"Interleukin-31 plays an important role in generation of pruritus in atopic dermatitis and can reduce patients quality of life and exacerbate atopic dermatitis by establish the itch-scratch cycle," said Hanifin.

The results showed dose-dependent decreases in the pruritus VAS for the three of the four nemolizumab groups versus placebo. The pruritus VAS declined by 20.1% in the placebo group increasing to 41.5%, 60.5% and 61.2% in the three nemolizumab groups (P=0.0027 to P<0.0001). A similar dose-dependent pattern emerged from an analysis of the proportion of patients who achieved at least 50% improvement in the pruritus VAS.

Hanifin reported that 4.7% of the placebo group achieved ISGA ≤1 at week 12 versus 21% (P=0.0488) and 16.3% (P=0.1593) of patients treated with higher doses of nemolizumab.

Sleep parameters also improved in patients treated with nemolizumab. Average sleep onset latency decreased 15 to 20 minutes at 4 weeks from baseline means of 31 to 42 minutes across the nemolizumab groups, whereas latency increased slightly in the placebo group before returning to baseline. Total sleep time increased significantly in all of the nemolizumab groups (P=0.0037 to P=0.0003 versus baseline means of 5.2 to 5.5 hours) but did not change in the placebo group.

The frequency and severity of adverse events did not differ substantially between the placebo- and nemolizumab-treated patients.

"The improvement of dermatitis scores was attributed to interruption of the itch-scratch cycle," Hanifin said. "This is the first study demonstrating that inhibition of pruritus leads to improved dermatitis."