Neurokinin‐1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial

Abstract

Atopic dermatitis (AD) is a relapsing and remitting disease characterized by intense pruritus that can lead to scratching and eczematous lesions that vary in extent and severity. 1 Over 60% of AD cases are mild, characterized by slight erythema, induration and lichenification. 2,3 Chronic pruritus, pruritus lasting more than 6 weeks, has been reported by 91% of AD patients. 4,5 The pathophysiology of AD is driven by a combination of skin barrier dysfunction, neuroinflammation and immune system dysregulation. 6,7 Elevated substance P (SP) is found in both serum and lesional skin of patients with AD. 5,8,9 SP, a neuropeptide released from the activation of sensory neurons, preferentially binds to the neurokinin-1 (NK-1) receptor and is a known itch mediator. 5 Tradipitant (VLY-686), a novel NK-1 receptor antagonist, has the potential to reduce itch related to AD through inhibition of SP-mediated itch signalling. We examined the efficacy and safety of tradipitant, in reduction of chronic pruritus in adults with mild to severe AD.EPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted at 74 US centres. Altogether 375 patients [mean (SD): age, 41.8 (15.0) years; sex, 243 (64.8%) female] were randomly assigned to tradipitant (n = 188) or placebo (n = 187). Although there was a numerical benefit in the tradipitant group over placebo, EPIONE did not meet its primary endpoint of reduction in pruritus [Least Squares (LS) Mean difference (95% CI), À0.2 (À0.8 to 0.4), P = 0.567]. However, robust antipruritic effect was observed in patients with mild lesion severity [rated 1 or 2 by the validated Investigator Global Assessment for Atopic Dermatitis at baseline À1.6 (À2.9 to À0.3), P = 0.015; Figs 1 and 2a]. This result was confirmed by daily diary [À2.09 (À3.31 to À0.87), P = 0.001] and observed after one full day of treatment [Fig. 2b, À0.61 (À1.21 to À0.01), P = 0.0457]. Improvement in nighttime sleep was also observed in mild AD [À1.46 (À2.60 to À0.32) P = 0.013].The most frequent treatment-emergent adverse events (TEAEs) were mild to moderate. There were no common TEAEs identified in the treatment arm, defined by >5% incidence.Tradipitant treatment resulted in a clinically meaningful reduction in patient-reported worst itch and sleep disturbance Figure 1 Worst Itch-Numeric Rating Scale (WI-NRS) change by week. Mild atopic dermatitis (AD) patients have greater improvement in worst itch after tradipitant treatment. Forest plots of the analysis of intent-to-treat and IGA 1,2 WI-NRS change by week. Plotted as least squares mean difference and 95% CI after tradipitant or placebo treatment.

Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

“…In a phase III study with 375 patients, another novel NK1R antagonist tradipitant (VLY-686) (EPIONE study), missed the primary end point of reduction in pruritus. However, reduction of 50% in SCORAD from baseline was noticed in mild forms of AD 206 .…”

A Systematic Review of Atopic Dermatitis: The Intriguing Journey Starting from Physiopathology to Treatment, from Laboratory Bench to Bedside

“…In the preliminary phase, studies that aim to evaluate the effect of targeting pruritus through the inhibition of P2X purinoreceptors 3, neurokinin 1 receptor or substance P are also interesting [ 86 , 87 , 88 ].…”

Pruritogens in pemphigoid diseases: Possible therapeutic targets for a burdensome symptom

“…104 Other NK1R inhibitors, such as orvepitant and tradipitant, have been tested in clinical trials for the pruritus associated with epidermal growth factor receptor inhibitor and atopic dermatitis, respectively; however, neither of them demonstrated significant improvement of pruritus over placebo. 105,106 In BP, both protein levels in bister fluid and the number of infiltrating positive cells for substance P are increased (Figure 1 and Table 1). 39,107 Importantly, the number of the substance P-positive cells in the dermis correlate with the severity of the pruritus.…”