Phase 3 Study Aims to Confirm Benefit of Dual Orexin–Receptor Antagonist TS-142 in Insomnia

Makoto Uchiyama MD, PhD

INSOMNIA IS A DISORDER that can lead to significant daytime impairment over the course of months or years. Orexins, neuropeptides first discovered in 1998, play an important role in maintaining wakefulness and regulating the sleep-wake cycle.^1,2 To keep individuals awake, it is theorized that these neuropeptides stimulate other neurons to release neurotransmitters that promote alertness, such as dopamine, serotonin, and norepinephrine, making them a therapeutic target.³

TS-142, a novel and potent dual orexin receptor antagonist designed by Taisho Pharmaceutical to be absorbed quickly with a short plasma half-life, is being assessed in a phase 3 study (NCT05453136) that is expected to enroll 540 patients with insomnia. This multicenter, double-blind, parallel-group study will randomly assign patients to doses of 5 or 10 mg of TS-142, or placebo, for a 2-week treatment period, with differences in subjective sleep latency (sSL) as the primary end point.

The trial began recruitment in August 2022 and is expected to conclude in early 2024. For inclusion in the study, patients must be 18 years or older, be outpatients, and have a diagnosis of insomnia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition⁴ (TABLE²). Those whose diagnosis falls outside the category of insomnia— including those with sleep-wake disorders—will be excluded from the study. Additionally, the study will not include patients with psychiatric disorders such as depression, schizophrenia, or anxiety, as well as those who have difficulty sleeping because of other medical problems.²

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In addition to sSL, the study will assess other secondary measures such as subjective sleep efficiency, defined as the percentage of subjective total sleep time (sTST) in total amount of time from bedtime to wake-up time. Additionally, other outcomes include difference in sTST, difference in subjective wake time after sleep onset (sWASO), and difference of subjective number of awakenings.

Previously, TS-142 showed promise as a therapeutic for insomnia in a phase 2, double-blind, randomized controlled trial (NCT04573725) conducted by Makoto Uchiyama MD, PhD, the director general at Tokyo Adachi Hospital, and professor of psychiatry at Nihon University School of Medicine, et al. In the study, 24 patients were randomly assigned to either placebo or TS-142 in single doses of 5, 10, or 30 mg in 1 of 4 sequences, with a 7-day washout period between treatments. The primary efficacy end points were latency to persistent sleep (LPS) and WASO, as measured by polysomnography.⁴

At the conclusion of the study, all of the groups treated with TS-142 had significantly improved LPS. The respective least-squares mean differences from placebo were –42.38 min (95% CI, –60.13 to –24.63), –42.10 min (95% CI, –60.02 to –24.17), and –44.68 min (95% CI, –62.41 to –26.95) for the 5-, 10-, and 30-mg groups, respectively (P < .001 for all doses). Although there was no dose-related trend for LPS, there was one observed regarding the effect on treatment on WASO. The least-squares mean differences in WASO between placebo and the 5-, 10-, and 30-mg TS-142 groups were –27.52 min (95% CI, –46.90 to –8.14), –35.44 min (95% CI, –55.02 to –15.87), and –54.69 min (95% CI, –74.16 to –35.23), respectively.

“The effect of TS-142 on sleep maintenance (WASO) showed a dose-related trend, which may reflect the pharmacokinetic properties of TS-142,” Uchiyama et al wrote.⁵ “It is assumed that the plasma concentration of TS-142 reaches the minimal effective concentration to exert sleep induction relatively rapidly and that this concentration is maintained for several hours. We speculate that the period of time that the effective concentration is exceeded increases with increased TS-142 dosing, which would explain the dose-related trend on WASO. Both subjectively and objectively measured WASO demonstrated improved sleep maintenance with TS-142 treatment compared with placebo. Therefore, TS-142 is expected to be an effective treatment option in patients experiencing certain sleep maintenance disturbances.”

In terms of safety, there were no clinically relevant serious treatment-related adverse events (AEs) observed, and no patients withdrew because of AEs. The only AEs that occurred in 2 or more patients were somnolence and nightmares, which were considered to have a causal relationship with the study drug. All AEs were of mild severity, apart from 1 case of moderate rhabdomyolysis in the 30-mg TS-142 group; however, this was considered unrelated to the study drug. Notably, there were no changes in vital signs, electrocardiogram findings, or laboratory tests.

TS-142 is also being evaluated in a long-term phase 3 study (NCT05461352) of 300 participants with insomnia. This open-label trial is looking primarily at the incidence of AEs in patients treated with the agent for 1 year, with secondary outcomes that include subjective sleep efficacy, sSL, sTST, and sWASO.

REFERENCES
1. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95(1):322-7. doi:10.1073/pnas.95.1.322
2. Sakaurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviors. Cell. 1998;92(4):573-585. doi:10.1016/S0092-8674(00)80949-6
3. Newsom R. Orexins. Sleep Foundation website. Updated April 29, 2022. Accessed March 7, 2023. https://www.sleepfoundation.org/sleep-aids/orexins
4. Phase III study of TS-142 in patients with insomnia. Clinicaltrials.gov. Updated October 6, 2022. Accessed March 3, 2023. https://clinicaltrials.gov/ct2/show/study/NCT05453136
5. Uchiyama M, Kambe D, Imadera Y, Kajiyama Y, Ogo H, Uchimura N. Effects of TS-142, a novel dual orexin receptor antagonist, on sleep in patients with insomnia: a randomized, double-blind, placebo-controlled phase 2 study. Psychopharmacology (Berl). 2022;239(7):2143-2154. doi:10.1007/s00213-022-06089-6