The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 antagonist, in patients with idiopathic and diabetic gastroparesis. METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary. RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12. CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).

Simulated driving performance in healthy adults after night-time administration of 20 mg tasimelteon.

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.

Tasimelteon safely and effectively improves sleep in Smith-Magenis syndrome: a double-blind randomized trial followed by an open-label extension.

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.

Gesicles packaging dCas9-VPR ribonucleoprotein complexes can combine with vorinostat and promote HIV proviral transcription.

Despite the success of combination antiretroviral therapy (cART) in HIV treatment, a cure for HIV remains elusive. Scientists postulate that HIV latent reservoirs may be a vital target in curative strategies. Vorinostat is a latency-reversing agent that has demonstrated some effectiveness in reactivating latent HIV, but complementary therapies may be essential to enhance its efficacy. One such approach may utilize the CRISPR-Cas9 system, which has evolved to include transcriptional activators such as dCas9-VPR. In this study, we explored the effects of combining vorinostat coupled with gesicle-mediated delivery of dCas9-VPR in promoting the transcription of integrated HIV proviruses in HIV-NanoLuc CHME-5 microglia and J-Lat 10.6 lymphocytes. We confirmed that dCas9-VPR ribonucleoprotein complexes can be packaged into gesicles and application to cells successfully induced HIV transcription through interactions with the HIV LTR. Vorinostat also induced significant increases in proviral transcription but generated inhibition of cellular proliferation (microglia) or cell viability (lymphocytes) starting at 1,000 nM and higher concentrations. Experiments combining dCas9-VPR gesicles and vorinostat confirmed the enhanced transcriptional activation of the HIV provirus in microglia but not lymphocytes. Thus, a combination of dCas9-VPR gesicles with other latency-reversing agents may provide a complementary method to activate latent HIV in future studies utilizing patient-derived cells or small animal models.

Enrichment of Patients With Ehlers Danlos Syndrome in Idiopathic Gastroparesis-A Gene Set Enrichment Analysis.

INTRODUCTION: Ehlers Danlos syndrome (EDS) is a heritable disorder of the connective tissue usually inherited as an autosomal dominant trait. We observe an enrichment of EDS cases in a gastroparesis clinical study. METHODS: We explored the frequency of EDS cases in 2 consecutive gastroparesis clinical studies. To explore the genetic surrogates of EDS, we have performed whole-genome sequencing analysis and we focused the analyses on the frequencies of consequential variants in core EDS genes. RESULTS: We report a significant enrichment of EDS cases in a set of patients with gastroparesis (14/686 vs 1/5,000 OR 104 (confidence interval 13.7-793.3) P value <0.0001). We report a significant enrichment of variants in EDS genes in patients with idiopathic gastroparesis. DISCUSSION: The enrichment may be suggestive of converging pathways at the heart of etiology or predisposing patients to EDS with gastroparesis.

Once-daily tasimelteon (VEC-162) for jet lag following transmeridian travel: A multicenter, randomized, double-blind, placebo-controlled trial.

Jet Lag Disorder is a Circadian Rhythm Sleep-Wake Disorder resulting from a misalignment of the endogenous circadian clock and the sleep and wake pattern required by a change in time zone. Jet lag is most severe following eastward travel. This multicenter, randomized, placebo-controlled clinical trial (JET) assessed the physiological mechanism of jet lag induced by a real-life transmeridian flight and evaluated the efficacy of tasimelteon-a circadian regulator acting as a dual melatonin receptor agonist, in the treatment of Jet Lag Disorder (JLD). Tasimelteon-treated participants slept 76 min longer on Night 3 during their second trip (evaluation phase) as compared to their first (observational phase). Over the three travel nights evaluated, transmeridian jet travelers in the tasimelteon group slept 131 min more (TST2/3) than those in the placebo group. The JET study demonstrated clinically meaningful improvements in nighttime sleep and daytime alertness in both objective and subjective measures as well as global functioning after a real-world flight. These results suggest that tasimelteon can be an effective therapeutic tool to treat JLD in the context of transmeridian travel.