Opioid receptor agonist difelikefalin disappoints in AD

Significant itch reduction was achieved with difelikefalin only in those patients with atopic dermatitis (AD) having an itch-dominant phenotype. However, the phase 2 KARE trial failed to meet its primary endpoint in the whole study population of mild-to-moderate AD patients.

Difelikefalin is in development for the treatment of pruritus in chronic diseases [1]. The selective kappa-opioid receptor agonist has recently been granted FDA approval for the reduction of itch in haemodialysis patients.

The phase 2 KARE trial (NCT04018027) enrolled just above 400 patients to assess difelikefalin for itch in AD over 12 weeks of treatment [2]. The study design comprised 3 groups of different concentrations of difelikefalin (i.e. twice daily oral 0.25 mg, 0.5 mg, or 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 body surface area (BSA), representing those with an itch-dominant AD phenotype of the disease. “In terms of BSA or Eczema Area and Severity Index (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).

Although the highest dose of the study drug demonstrated a significant difference in efficacy at some timepoints 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, but 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.

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   1. Fishbane S, et al. N Engl J Med 2020;382(3):222–232.
   2. Kim BS. Oral difelikefalin reduces pruritus in atopic dermatitis. D3T01.1D, EADV Congress 2021, 29 Sept–2 Oct.

 

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Posted on 17 November, 202118 November, 2021