Oral Difelikefalin Reduces Pruritus in Atopic Dermatitis

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Introduction and Objective
• Pruritus is the central symptom in atopic dermatitis (AD) 1 • Patients with mild-to-moderate AD frequently exhibit severe itch, and treatments that specifically target AD-related pruritus are lacking 1,2 • Difelikefalin (DFK), a novel, selective kappa-opioid receptor (KOR) agonist, is being developed for chronic pruritic conditions 3,4 -In August 2021, IV DFK received approval from the US Food and Drug Administration for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis 5 • Here, we present a mouse model of AD which was used to test the effects of DFK on itch and lesional severity • Results are also presented from a phase 2 study of oral DFK in subjects with AD and moderate-tosevere pruritus
BMI, body mass index; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index.
• Approximately two-thirds (64%) of subjects had BSA <10% LS means from mixed effects model with repeated measures (MMRM) with terms for treatment, week, week by treatment interaction, baseline score, and AD severity.Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption.I-NRS scores after use of rescue are set to missing and then imputed with MI.BL, baseline; ITT, intent to treat; LS, least squares.LS means from MMRM with terms for treatment, week, week by treatment interaction, and baseline score.Missing data imputed using multiple MI under MAR assumption.I-NRS scores after use of rescue are set to missing and then imputed with MI.

LS Means Over Time
• Significant improvement in itch was observed at week 12 with the combined DFK group compared with placebo • Significant improvement was evident as early as day 2 14  • TEAEs were mostly mild or moderate in severity (~95%)

LS Means Over Time
• Most discontinuations were due to gastrointestinal-related TEAEs • Serious TEAEs occurred in 1 subject with hypovolemia and acute kidney injury (DFK 1.0 mg), 1 subject with hyponatremia (DFK 1.0 mg), 1 subject with nephrolithiasis (DFK 0.5 mg), and 1 subject with costochondritis (DFK 0.25 mg) -All SAEs were deemed unrelated to study drug by the investigator 16 Safety analyses performed in the safety population, defined as all randomized subjects who received ≥1 dose of study drug based on actual treatment received.TEAE, treatment-emergent adverse event.17 Safety analyses performed in the safety population, defined as all randomized subjects who received ≥1 dose of study drug based on actual treatment received.

Most Commonly Reported TEAEs (ITT Population)
*Includes preferred terms abdominal pain, abdominal pain upper, abdominal discomfort.† Includes preferred terms hypertension and blood pressure increased.

Conclusions
• In a mouse model of AD: -A rapid and significant anti-pruritic effect of DFK was observed independently of observable effects on skin inflammation -Analyses in this model indicate that expression and activation of the DFK target receptor is on sensory neurons • In the phase 2 clinical study that includes approximately two-thirds of subjects with itchdominant AD (BSA <10% and moderate-to-severe pruritus): -DFK demonstrated a significant and clinically meaningful reduction in pruritus -DFK was well tolerated • Taken together, these findings support the role of DFK as an antipruritic agent that may be best suited for patients with itch-dominant AD