Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials

Yuichi Inoue, Makoto Uchiyama, Hideo Umeuchi, Koichi Onishi, Hiroki Ogo, Iwao Kitajima, Isao Matsushita, Izumi Nishino, Naohisa Uchimura, Yuichi Inoue, Makoto Uchiyama, Hideo Umeuchi, Koichi Onishi, Hiroki Ogo, Iwao Kitajima, Isao Matsushita, Izumi Nishino, Naohisa Uchimura

Abstract

Background: The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy.

Methods: We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study.

Results: Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2.

Conclusions: The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments.

Trial registration: ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2).

Keywords: Clinical trial; ESS; Enerisant; Histamine; MWT; Narcolepsy; TS-091.

Conflict of interest statement

Yuichi Inoue reports that he and his department have received research support (grants) from Philips Japan Co., Ltd. and KOIKE Medical Co., Ltd.; in addition, he has provided speaking and consulting services to and received personal fees from Eisai Co., Ltd., provided speaking services and received personal fees from Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., and MSD K.K.; and provided consulting services and received personal fees from Taisho Pharmaceutical Co., Ltd. Makoto Uchiyama reports that he and his department have received grants from Astellas Pharma Inc., Eisai Co., Ltd., Meiji Seika Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Merck Sharp & Dohme, Pfizer Inc., Sanofi S.A., Takeda Pharmaceutical Co., Ltd., and Yoshitomiyakuhin Corporation; in addition, he has provided consulting services and received personal fees from Janssen Pharmaceutical K.K., Kao Corporation, Shionogi & Co., Ltd., and Taisho Pharmaceutical Co., Ltd. Hideo Umeuchi, Koichi Onishi, Hiroki Ogo, Iwao Kitajima, Isao Matsushita, and Izumi Nishino are employees of Taisho Pharmaceutical Co. Ltd. Naohisa Uchimura reports receiving grants from Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Merck Sharp & Dohme, and Takeda Pharmaceutical Co., Ltd.; in addition, he has provided consulting services to and received personal fees from Taisho Pharmaceutical Co., Ltd.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Study design for Study 1 (a) and Study 2 (b)
Fig. 2
Fig. 2
Simulation of H3 receptor occupancy after enerisant administration. The time-course of histamine H3 receptor occupancy after a single oral administration of enerisant was simulated, and the time to maintain 90% of H3 receptor occupancy was calculated. In the simulation, pharmacokinetic data obtained from the enerisant single ascending dose study and the pharmacodynamics data obtained from the H3 receptor occupancy study of enerisant [9] were used. Phoenix WinNonlin (ver.6.2) and Microsoft Excel 2010 were used as the analysis software
Fig. 3
Fig. 3
Disposition of subjects for Study 1 (a) and Study 2 (b)
Fig. 4
Fig. 4
Secondary endpoint outcomes: total ESS score changes in Study 1 and Study 2. 95% confidence interval

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Source: PubMed

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