Opioid receptor agonist benefits patients with itch-dominated AD

For atopic dermatitis with less than 10% body surface area involvement, difelikefalin has exhibited significant efficacy in itch reduction.

Difelikefalin: recent FDA approval for itch reduction

The phase 2 KARE trial (NCT04018027) enrolled just above 400 patients to test difelikefalin, a selective kappa-opioid receptor agonist, for itch in AD over 12 weeks of treatment¹. Difelikefalin has recently been granted FDA approval for the reduction of itch in haemodialysis patients.

The study design comprised 3 groups of different concentrations of difelikefalin (i.e. twice daily oral 0.25 mg, 0.5 mg, 1.0 mg) plus a matching placebo arm. Only emollient use was allowed, all other related medication was washed out. The primary endpoint was change in the weekly mean score of daily itch numeric rating scale (I-NRS). Furthermore, an analysis was planned of the subpopulation of patients with <10% of BSA representing those with an itch-dominant AD phenotype of the disease. 

At baseline, the mean age was 41 years, with about 2 thirds of women. “In terms of BSA or EASI score, we see numbers consistent with what would be mild-to-moderate in this population,” explained Prof. Brian Kim (Washington University School of Medicine, MO, USA).

The KOR antagonist may best suit patients with itch-dominant AD

Although the highest dose of the study drug demonstrated a significant difference in efficacy at some time-points during the trial, at 12 weeks none of the groups reached the primary endpoint.

The itch dominant subgroup (BSA<10%) comprised 257 participants in whom the mean I-NRS at baseline was around 7.6 and Dermatology Life Quality Index about 11.7. “These patients may have milder disease based on objective disease criteria; in terms of itch and quality of life they are more on the severe end of the disease,” Prof. Kim stated. For them, a significant improvement was found as of day 2 and the efficacy versus placebo was significant for all doses (P=0.039). The proportion that experienced a clinically meaningful improvement of ≥4 points in I-NRS was significantly greater over placebo in the 0.5 mg dosage arm.

As for safety, the most adverse events were mild to moderate with 2 serious adverse events, not adjudicated to the study drug. Most commonly reported was abdominal pain. “These findings support the role of difelikefalin as an antipruritic agent that may be best suited for patients with itch-dominant AD, which needs to be studied much more in the near future,” Prof. Kim summarised.