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.

Importance: Safe oral systemic treatments are needed to treat itch associated with atopic dermatitis (AD). Objective: To examine the efficacy and safety of tradipitant, a neurokinin-1 receptor antagonist, in adults with mild to severe AD. Design, Setting, and Participants: EPIONE was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from July 09, 2018 to December 27, 2019 at 74 US centers. Patients were adults 18 years or older with worst itch rated ≥7 on the Worst Itch Numerical Rating Scale (WI-NRS) and ≥ 1% body surface area of AD involvement at screening. Interventions: Patients were randomly assigned (1:1) to twice-daily oral placebo or tradipitant (85 mg) for 8 weeks. Main Outcomes and Measures: The primary endpoint was mean improvement in WI-NRS (baseline to Week 8). Secondary endpoints included disease severity improvement measured by SCORing Atopic Dermatitis (SCORAD) index, the Eczema Area and Severity Index (EASI), and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-ADTM). Results: 341 patients (mean [SD]: age, 41.8 [15.0] years; sex, 243 [64.8%] female) were randomly assigned to placebo (n = 187) or tradipitant (n = 188). EPIONE did not meet its primary endpoint of reduction in pruritus (LS Mean difference (95% CI), -0.2 (-0.8 to 0.4), P = 0.567). However, robust antipruritic effect was observed in patients with mild lesion severity (rated 1 or 2 by the vIGA-AD at baseline, -1.6 (-2.9 to -0.3), P = 0.015). This result was confirmed by daily diary (-2.09 (-3.31 to -0.87), P = 0.001) and observed after one full day of treatment (-0.61 (-1.21 to -0.01), P = 0.0457). Treatment-emergent adverse events (TEAEs) were reported in 63 of 188 (33.5%) tradipitant patients and 43 of 187 (23.0%) placebo patients. TEAEs with > 2% incidence and twice that of placebo included diarrhea (VLY-686 = 5 (2.7%), PBO = 1 (0.5%)), fatigue (VLY-686 = 5 (2.7%), PBO = 0 (0.0%)), and worsening of AD (VLY-686 = 4 (2.1%), PBO = 1 (0.5%)). Conclusions and Relevance: During 8 weeks of treatment, tradipitant was well-tolerated for all study participants, but did not significantly improve worst itch in the overall study population. However, in patients with mild AD at baseline, tradipitant was observed to have a large and rapid antipruritic effect. These data support the role of neurokinin-1 antagonism and substance P signaling in chronic pruritus related to mild AD. If these findings replicate in the on-going phase 3 study, EPIONE2, tradipitant may represent a promising new oral therapy for these mild AD patients.

We conducted an observational research study to collect information on sleep–wake patterns from participants with a confirmed status of the cryptochrome circadian clock 1 (CRY1) splicing variant, CRY1Δ11 c.1657 + 3A > C, and their controls, defined as wild-type (WT) family members. Altogether, 67 participants were enrolled and completed this study in Turkey, recruited from a list of families with at least one CRY1-confirmed member. We measured sleep–wake patterns and metabolic output, specifically time and frequency of bowel movements, for all participants by daily post-sleep diaries over 28 days. The sleep diary measured self-reported bed time, wake time, midpoint of sleep, and latency to persistent sleep (LPS), and accounted for naps and awakenings for religious purposes. Wake time and midpoint of sleep were significantly later in the CRY1Δ11 variant group versus WT, and LPS was significantly greater in participants in the CRY1Δ11 variant group. The mean bed time on all nights of sleep was later in participants with a CRY1Δ11 variant versus WT. Additionally, participants with a CRY1Δ11 variant had significantly affected metabolic outputs, measured by later bowel movements than WT participants. These results demonstrate that, on average, individuals with the studied splicing variant experience pronounced delays in sleep period and circadian-related metabolic processes.

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Background: Atopic dermatitis (AD) is a heritable and heterogeneous inflammatory chronic skin disorder. Utilizing decision tree/ supervised learning of extensive clinical, molecular and genetic data, we aimed to define distinct AD endotypes. Methods: Deep phenotyping and whole-genome sequencing was performed on samples obtained from participants of EPIONE, a phase III study in AD patients with severe pruritus: mild (23%) to moderate (64%) and severe (13%) as determined by validated Investigator Global Assessment scale for Atopic dermatitis (vIGA-ADTM). Three categories of analysis were performed: clinical associations, lab value associations (EOS, IgE, cytokines) and genetic analysis of whole-genome sequencing data Results: Based on a decision tree, we found that mild AD presents with fewer lesions with mild erythema and minimal induration/papulation or oozing/crusting. In contrast, severe AD presents with a larger number of erythematous lesions associated with significant induration/papulation or oozing/crusting. We observe significant differences between severity and eosinophil counts (p < 0.001), IgE (p < 0.001) and Filaggrin (FLG) LOF frequency (OR 2.3 CI 1.6-3.2 p < 0.0001) as well as interleukin pathway genes, specifically IL5RA variants differentiating the groups. Conclusion: Our results suggest significant differences between severity groups across a number of features appear to constitute distinct endotypes with likely distinct causative factors. Differing underlying pathophysiologies indicate endotype knowledge is critical to help guide therapeutic approaches to AD.