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.

Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18–73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST 2/3 ), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon ( n = 160) or placebo ( n = 160). Tasimelteon treatment increased TST 2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by −15.1 min (95% CI −26.2 to −4.0, P = 0.0081). Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

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.

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