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The genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin ( FLG ) is an essential gene in the epidermal barrier formation s. Loss-of-function (LOF) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. In this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG LOF status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG LOF variants. Having two or more FLG LOF variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely EDC variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus

Tasimelteon is a dual melatonin 1 and melatonin 2  receptor agonist. Tasimelteon is the first and only approved medicine to treat a circadian rhythm disorder. In this Phase III trial, the efficacy and safety of tasimelteon was studied in primary insomnia characterized by difficulty falling asleep. A randomized, double-blind, placebo-controlled, multi-center study investigated 20 mg or 50 mg tasimelteon vs placebo in 322 patients with primary insomnia over a 5-week double-blind treatment interval using polysomnography(PSG) measures of sleep. Patients underwent PSGs on Nights 1, 8, 22 and 29. Entry criteria emphasized enrollment of primary insomnia patients with a confirmed difficulty falling asleep. Subjective sleep latency was ≥ 45 minutes based on sleep history and sleep diary and, patients had a mean latency to persistent sleep (LPS) of ≥30 minutes on two consecutive screening PSG nights with no night having an LPS less than 20 minutes. On the primary end point, the mean improvement in LPS from baseline to the average of Nights 1 and 8 was 44.9 minutes (20 mg) and 46.3 minutes (50 mg) versus 28.2 minutes (placebo) (p < 0.001). Improvements in LPS persisted through the follow-up time points (Nights 22 and 29, p < 0.01). Tasimelteon use was not associated with cognitive or mood changes, and neither rebound nor withdrawal effects were observed after discontinuation. Tasimelteon improved sleep from the first night of treatment, and the effect continued for the duration of the study. Tasimelteon was well-tolerated with no adverse next-day residual effects observed. The results of the study strongly suggest that tasimelteon may be an effective therapeutic tool in the treatment of individuals with chronic sleep onset insomnia.

Abstract Introduction Major Depressive Disorder (MDD) is often associated with insomnia and it has been hypothesized that circadian rhythm disruption may be involved in the etiology of MDD. We have conducted a large clinical study evaluating the effects of the circadian regulator tasimelteon on depressive symptoms in patients with MDD. Methods 507 patients with MDD were enrolled in a double masked placebo controlled study randomized on either tasimelteon 20 mg (n=254) or placebo (n=253). Patients were assessed at baseline and weekly for 8 weeks on a number of depression scales including the Hamilton Depression Scale (HAMD). Results Tasimelteon and placebo treated patients appeared to improve similarly from baseline by 8.1 and 7.8 points respectively on the HAMD scale (pvalue =0.57). An analysis by race however revealed a significantly positive effect of tasimelteon among African American patients. Out of 507 randomized patients 166 (32.7%) were African American (AA) of which 78 were treated with tasimelteon and 88 with placebo. At 8 weeks African American MDD patients treated with tasimelteon improved by 9.9 points on the HAMD scale as compared to 6.9 points for the placebo treated patients (pvalue =0.018). In a responder analysis (improvement in the HAMD scale of 50% or greater from baseline) 59% of tasimelteon treated patients improved as compared to 30% of placebo treated patients (pvalue =0.0019). Conclusion Tasimelteon 20 mg was shown to improve symptoms of depression in African American patients with MDD in a meta-analysis of a large MDD clinical study which may suggest a circadian component in the etiology and treatment of Major Depression. Support (If Any) This work was supported by Vanda Pharmaceuticals Inc.

Abstract Introduction Individuals diagnosed with Smith-Magenis Syndrome (SMS), a rare genetic disorder due to a deletion on chromosome 17, typically exhibit self-injurious and aggressive behaviors and disrupted nighttime sleep (i.e., difficulties falling asleep or frequent, prolonged nighttime awakenings). The associated nighttime sleep disturbances may be related to the observed inappropriate timing of the endogenous melatonin secretion during the daytime in this population. Methods There were 12 individuals (7 male) diagnosed with SMS, ages 16–38 years (mean + SD = 23.7 ± 7.3 years), who were assessed during a ~6-week baseline phase followed by an open-label treatment phase (tasimelteon, 20 mg capsule, nightly 1 h prior to bedtime) for 9–36 weeks. Parents rated their child’s nighttime sleep quality (1=Poor to 5= Excellent) every morning and rated their child’s behavior using the Aberrant Behavior Checklist-Community (ABC-C), a 58-item checklist with a 4-point rating scale (0=“not at all a problem” to 3= “the problem is severe in degree”), every 3–6 weeks during both phases of the study. A paired Student′s t-test was used to analyze the data. Results In comparison to the baseline phase (mean change; pvalue), scores of parent-reported sleep quality significantly increased (+0.51; 0.0105) and total score on the ABC-C significantly decreased (-15.89; 0.0006) during treatment phase, including four ABC-C subscales, “Hyperactivity, Noncompliance” (-5.96; 0.0049), “Irritability, Agitation, Crying” (-5.62; 0.0004), “Lethargy” (-2.10; 0.0384) and “Stereotypic Behavior” (-1.24; 0.0049). The remaining ABC-C subscale, “Inappropriate Speech”, exhibited a decreasing trend (-0.96; 0.0754). Conclusion Parents of children with SMS reported improvement in sleep quality and decrease in aberrant behaviors during treatment with tasimelteon, as compared to baseline. Although not collected under placebo-controlled conditions, these data suggest that nightly tasimelteon treatment may alleviate the nighttime sleep disruption in individuals diagnosed with SMS and may impact daytime aberrant behaviors. Support (If Any) This work was supported by Vanda Pharmaceuticals Inc.

Abstract Introduction Circadian physiology has been hypothesized to play a role in the etiology of Major Depression and may affect symptom expression and response to treatment. We have studied markers of circadian physiology in a large cohort of patients with MDD and have identified differences of the expression of the circadian timing system between African Americans and Caucasians. Methods Patients diagnosed with MDD (DSM-IV), including 94 African Americans (70 female) ages 19–61 years (mean + SD = 41.0 ± 11.7 years) and 235 Caucasians (158 female) ages 18–65 years (42.9 ± 13.5 years) participated in this study. Patients collected saliva samples at home every hour for 9 hours starting 5 hours prior to their habitual bedtime. Participants recorded date and clock time of each sample and were instructed to avoid bright light and wear amber-lens (blue-light filtering) goggles throughout collection. Samples were frozen until assayed for melatonin. Melatonin onset (MO) was defined as the interpolated clock time between 2 consecutive samples when melatonin concentrations rose above 4 pg/mL. The sample clock times for collections performed during daylight saving time were not adjusted (-1 hour) to standard time. A paired Student′s t-test was used to analyze the data. Results The mean Melatonin onset (MO) clock time was at 9:04 PM in the African American-MDD population as compared to 9:35 PM in the Caucasian-MDD population. The difference of 31 minutes between the two populations was statistically significant (pvalue =0.0229). Conclusion The timing of melatonin secretion in an African American-MDD population occurred at an earlier time relative to the Caucasian-MDD population. The role of this observation in the pathophysiology and treatment of MDD would need to be further investigated. Support (If Any) This work was supported by Vanda Pharmaceuticals Inc.

Abstract Introduction SMS is a rare neurodevelopmental disorder that manifests with craniofacial abnormalities, behavioral disturbances, and a severe sleep disorder. It has been reported that many SMS patients have an inverted melatonin secretion pattern (peaking during the daytime) although a small minority have near normal patterns. The goal of this study was to better characterize the intra- and inter-patient variability of melatonin secretion patterns and investigate a potential relationship with sleep behavior in SMS patients. Methods In this observational study, sleep behaviors of patients (N=8, 1 female, ages: 7 - 35) with SMS were characterized through caretaker surveys. On 3 separate occasions, patients had hourly serum melatonin levels sampled for 36 hours. From these data, peak serum melatonin concentration and time of peak concentration were determined. Inter- and intra-patient variability was characterized by zero lag correlation of the melatonin concentration timeseries across and within patients, respectively. The relationship between peak melatonin concentration, peak time, and sleep latency was analyzed by a generalized linear model, GLM. Results Peak melatonin concentrations varied across SMS patients with a range of 3.55pg/ml - 49.65pg/ml (mean 14.18 ± 15.19pg/ml). Time of peak melatonin concentrations ranged from 0400h-2100h (mean 1422 ± 6h). Correlation coefficients characterizing intra-patient variability ranged from -0.0098 to 0.89 (mean 0.55 ± 0.2533). Correlation coefficients characterizing inter-patient variability ranged from -0.75 to 0.79 (mean of 0.18 ± 0.52). Sleep latency ranged from 8.4min - 36.35min (mean of 21.99 ± 9.77 min). GLM analysis demonstrated a significant, positive effect of peak time with sleep latency (p=0.022). Conclusion Consistent with previous findings, our study confirms that SMS patients have abnormal circadian rhythms. Our work extends this body of literature by demonstrating a significant degree of inter-patient variability with relatively stable intra-patient variability. Preliminary evidence suggests that the timing of melatonin peak may be related to sleep onset latency. Support This work was supported by Vanda Pharmaceuticals Inc.

Abstract Introduction Smith-Magenis Syndrome (SMS) is a rare (1/15,000 - 25,000 births) neurodevelopmental disorder resulting from an interstitial deletion of chromosome 17p11.2, or from a point mutation in the RAI1 gene. Severe sleep disorder is almost universal in patients with SMS and poses a significant challenge to patients and their families. Tasimelteon improved sleep symptoms in a randomized, double-blind, two-period, crossover study; and here we show that this effect persists for up to four years in an open-label extension. To our knowledge, this is the largest interventional study of SMS patients to date. Methods Following the 4-week crossover study, all eligible participants had the option to enroll in an open-label extension. 31/39 (79.4%) of all individuals who participated in the efficacy study have continued on tasimelteon treatment. Participants in the open-label extension provided daily diary sleep quality (DDSQ), and daily diary total sleep time (DDTST) measures via parental post sleep questionnaire and characterized behavior using the Aberrant Behavior Checklist (ABC). Results In the open-label extension, tasimelteon continued to show improvement in the primary endpoints of 50% worst sleep quality (mean = 0.7, SD = 0.94) and 50% worst total nighttime sleep duration (mean = 53.3, SD = 59.01) when compared to baseline. Tasimelteon also improved overall sleep quality (mean=0.7, SD=0.83) and overall total nighttime sleep duration (mean = 51.9, SD=53.03). ABC scores also improved with tasimelteon (mean= -16.3, SD = 15.82). Conclusion Tasimelteon continues to demonstrate persistence in efficacy (longest approximately 4 years) with similar magnitudes observed in the 4-week crossover study for sleep quality and total sleep time. Interestingly, daytime behavior also demonstrates long-term improvement in patients with SMS treated with tasimelteon. These results further confirm tasimelteon as a novel therapy for the treatment of sleep disorders in patients with SMS and may provide benefit for behavioral symptoms. Support This work was supported by Vanda Pharmaceuticals Inc.

Abstract Introduction Jet Lag Disorder occurs when an individual’s circadian rhythms become misaligned due to rapid change in time zone that occurs after rapid transmeridian travel. By simulating such a time zone change in a lab setting, the effects of phase shifting can be studied in the absence of confounders that occur during travel including variable sleep deprivation and light exposure. Methods This observational study investigated the effects of a 5 hour and 8 hour sleep phase advance in 319 patients (5 hour: n=86; 8 hour: n=233). Patients went to bed 5 or 8 hours earlier than their usual bedtime and attempted to sleep for 8 hours, after a protocol of sleep hygiene. Overnight polysomnography was performed. Results Sleep efficiency (SE) was evaluated for each third of the night. A significant difference was demonstrated between the 5 hour and 8 hour phase advance in SE during each of the three thirds of the night: first third of the night SE (5 hour: 45.5%; 8 hour: 54.1%, p=0.02), second third of the night SE (5 hour: 53.4%; 8 hour: 24.8%; p<0.0001), and third third of the night SE (5 hour: 76.8%; 8 hour: 33.3%; p<0.0001). Conclusion This model of studying 5 to 8 hour phase advance as a model of Jet Lag was able to show significant differences in PSG-measured sleep efficiency between a 5 hour phase advance and an 8 hour phase advance during each third of the night. These results support this study design as a model to be used in developing therapeutics for the treatment of phase advance disorders including Jet Lag Disorder. Support (If Any) This work was supported by Vanda Pharmaceuticals Inc.

Purpose To assess the efficacy of tasimelteon to improve sleep in Smith–Magenis syndrome (SMS). Methods A 9-week, double-blind, randomized, two-period crossover study was conducted at four US clinical centers. Genetically confirmed patients with SMS, aged 3 to 39, with sleep complaints participated in the study. Patients were assigned to treatment with tasimelteon or placebo in a 4-week crossover study with a 1-week washout between treatments. Eligible patients participated in an open-label study and were followed for >3 months. Results Improvement of sleep quality (DDSQ50) and total sleep time (DDTST50) on the worst 50% of nights were primary endpoints. Secondary measures included actigraphy and behavioral parameters. Over three years, 52 patients were screened, and 25 patients completed the randomized portion of the study. DDSQ50 significantly improved over placebo (0.4, p  = 0.0139), and DDTST50 also improved (18.5 minutes, p  = 0.0556). Average sleep quality (0.3, p  = 0.0155) and actigraphy-based total sleep time (21.1 minutes, p  = 0.0134) improved significantly, consistent with the primary outcomes. Patients treated for ≥90 days in the open-label study showed persistent efficacy. Adverse events were similar between placebo and tasimelteon. Conclusion Tasimelteon safely and effectively improved sleep in SMS.

Motion sickness is characterized by nausea and vomiting among a constellation of symptoms. Symptom severity is dynamic and distressing. Most validated motion sickness scales are time-intensive and effortful, with alternative scales having uncertain performance or non-specific measures. A validated instrument allowing for facile, rapid assessment of core motion sickness symptom severity would therefore be valuable. We assessed the performance of the Motion Sickness Severity Scale (MSSS), a six-item questionnaire designed to measure real-time motion sickness symptoms. MSSS construct validity was assessed as a secondary analysis of data from 63 healthy participants without antiemetic treatment in a clinical trial (Unique Identifier = NCT03772340) conducted to evaluate the safety and efficacy of Tradipitant-a novel neurokinin-1 receptor antagonist-in the treatment of motion sickness. Clinical outcome assessments included the MSSS, the Patient Global Impression of Severity (PGI-S), and the Motion Sickness Assessment Questionnaire (MSAQ). The performance of the MSSS through Pearson correlation coefficients, within-group analysis of variance, empirical cumulative distribution functions, and Kolmogorov-Smirnov tests. The MSSS correlated very highly with the PGI-S (r = 0.93, p-value<0.0001) and highly with the MSAQ (r = 0.83, p-value<0.0001). Mean MSSS scores between increasing PGI-S severity levels increased significantly in all four increments (None-to-Mild: p-value = 0.006, Mild-to-Moderate: p-value<0.0001, Moderate-to-Severe: p-value = 0.006, Severe-to-Very-Severe: p-value = 0.002). There were statistically significant differences in MSSS score distributions stratified by PGI-S severity level, with higher MSSS scores associated with higher PGI-S severity levels and lower MSSS scores associated with lower PGI-S severity levels. The MSSS is a valid instrument for the assessment of the core motion sickness symptoms and is reflective of global disease severity. Implementation of the MSSS and comparable simplified, short questionnaires in motion sickness research will provide rapid and accurate measures of disease severity. These measures will enable further elucidation of motion sickness as an illness and inform the development and evaluation of motion sickness therapies.