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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.

Background: Gastroparesis is a serious medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain (Camilleri et al., 2018) . One-third of gastroparesis cases are related to uncontrolled diabetes (Young et al., 2020) . HBA1C levels in diabetic gastroparesis are not associated with more or less severe vomiting episodes (Parkman et al., 2016) . Individual signs and symptoms may occur more often or with greater severity in one population compared with the other due to the degree of diabetic control. Here we did a post-hoc analysis in a phase 2 study to see if there is a correlation between baseline HBA1C and baseline gastroparesis symptoms. Methods: Diabetic and idiopathic gastroparesis patients were screened to enroll in a phase 2 clinical trial. Patients with moderate to severe nausea and delayed gastric emptying would go onto be randomized to tradipitant 85mg BID or placebo for 4 weeks. Baseline clinical symptoms were measured by the Gastroparesis Core Symptom Daily Diary (GCSDD) . A post-hoc analysis was performed to correlate HBA1C with baseline gastroparesis symptoms in patients with diabetic gastroparesis. Results: Patients with diabetic gastroparesis and sufficient baseline data (n=106) had baseline nausea severity of 2.5 (1.175) and baseline HBA1C of 7.366 (1.373) . There was no correlation of baseline nausea and HBA1C levels for diabetic gastroparesis (0.021) . There was no correlation of average daily vomiting, fullness, early satiety, or abdominal pain and HBA1C levels in the diabetic gastroparesis population. Conclusion: Patients with diabetic gastroparesis experience the core signs and symptoms of gastroparesis. HBA1C levels in this population do not appear to be correlated with severity of nausea and vomiting and other core symptoms of gastroparesis. Disclosure J.L.Carlin: Employee; Vanda Pharmaceuticals, Inc. M.Fisher: Employee; Vanda Pharmaceuticals, Inc. . D.S.Madonick: Employee; Vanda Pharmaceuticals Inc. C.Kupersmith: Employee; Vanda Pharmaceuticals. P.Moszczynski: Employee; Vanda Pharmaceuticals, Inc. C.Xiao: None. G.Birznieks: Employee; Vanda Pharmaceuticals. M.H.Polymeropoulos: Other Relationship; Vanda Pharmaceuticals, Inc. .

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.

An impairment in next day driving performance has been reported for almost every drug currently United States Food and Drug Administration (FDA) approved for improvement of sleep in chronic and transient insomnia. Tasimelteon, a melatonin receptor agonist, demonstrated significant improvements in night-time sleep, daytime naps, and sleep timing in non-24-hr sleep-wake disorder (Non-24) by entraining these patients to a 24-hr day as measured by melatonin and cortisol rhythms. Given this new mechanism of action of entraining the biological clock, we conducted a study to evaluate the potential effect tasimelteon may have on the ability to operate a motor vehicle. The study was conducted in 48 healthy adult subjects using a randomised, double-blind, placebo and active (zopiclone 7.5 mg) controlled study with a 3-period cross-over design. Driving performance was assessed by measuring standard deviation of lateral position (SDLP) using the validated Cognitive Research Corporation Driving Simulator-MiniSim. The difference in least square mean SDLP for tasimelteon was 1.22 cm reflecting a non-significant increase in SDLP change from placebo (p = .1119). In contrast, treatment with the active control, zopiclone 7.5 mg, was associated with a meaningful and significant increase in SDLP, change from placebo for zopiclone was 4.14 cm (p < .0001). The lack of clinically meaningful and statistically significant finding with tasimelteon was further supported by the symmetry analysis, which showed the distribution of within-subject differences between tasimelteon and placebo was symmetric about zero. At the FDA-approved 20 mg dose to treat Non-24, tasimelteon did not impair next-day driving performance compared to placebo in adult healthy volunteers.

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.