Samelisant (SUVN-G3031), a histamine 3 receptor inverse agonist: Results from the phase 2 double-blind randomized placebo-controlled study for the treatment of excessive daytime sleepiness in adult patients with narcolepsy

Article

作者: Abraham, Renny ; Jayarajan, Pradeep ; Jasti, Venkat ; Ravula, Jyothsna ; Bogan, Richard K ; Pandey, Santosh Kumar ; Goyal, Vinod Kumar ; Dogiparti, Dhanunjay Kumar ; Chowdary Palacharla, Veera Raghava ; Jetta, Satish ; Nirogi, Ramakrishna ; Subramanian, Ramkumar ; Benade, Vijay ; Bogan, Richard K. ; Mohammed, Abdul Rasheed ; Shinde, Anil ; Kalaikadhiban, Ilayaraja

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices. Blocking of histamine 3 (H3) receptors has been demonstrated to be a viable approach for the management of symptoms of narcolepsy. Samelisant (SUVN-G3031) is a new H3 receptor inverse agonist. The efficacy, safety, tolerability, and pharmacokinetics of Samelisant in narcolepsy patients were evaluated in a phase 2, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT04072380). Patients diagnosed with narcolepsy according to the International Classification of Sleep Disorders criteria and having an Epworth Sleepiness Scale (ESS) score of ≥12 and a mean Maintenance of Wakefulness Test (MWT) time of <12 min across the 4 sessions at baseline were enrolled. The total study duration was up to 7 weeks, which included a screening period of 4 weeks, a treatment period of 2 weeks, and a safety follow-up 1 week after the last study drug administration. The primary efficacy measure was the change in total ESS score compared to placebo. Secondary and exploratory assessments included the Clinical Global Impression of Severity, MWT, Clinical Global Impression of Change, Patient Global Impression of Change and cataplexy rate. Safety assessments included monitoring adverse events (AEs) and laboratory assessments. Of the 426 patients screened, 190 were randomized. The safety and intention-to-treat population included 188 and 164 patients, respectively. A statistically significant treatment effect of Samelisant was observed on the primary endpoint, indicating improvements in EDS. The treatment's impact on EDS was also evident on the other patients' and clinicians' perspectives scales. The AEs reported in ≥5 % patients in any treatment groups were insomnia, abnormal dreams, nausea, and hot flush. Global phase 3 studies and long-term safety and efficacy assessments of Samelisant are planned to reaffirm the current findings.

2021-02-01·Behavioural brain research3区 · 心理学

Central histaminergic transmission modulates the expression of chronic nicotine withdrawal induced anxiety-like and somatic behavior in mice

3区 · 心理学

Article

作者: Jain, Nishant Sudhir ; Patel, Richa ; Vishwakarma, Prabhat Kumar ; Patel, Deepak

The present study investigated the plausible modulatory role of central histaminergic transmission on the expression of nicotine withdrawal induced anxiety and somatic behavior in mice. Abrupt cessation of chronic nicotine (2 mg/kg, i.p. × 3/day) treatment for 12 days to mice, expressed increased anxiety in light & dark test and total abstinence (somatic) score at 24 h post nicotine withdrawal time. The somatic signs includes a composite score of all behaviors such as grooming, rearing, jumping, body shakes, forelimb tremors, head shakes, abdominal constrictions, scratching, empty mouth chewing or teeth chattering, genital licking, tail licking. Mice exhibited higher expression to nicotine withdrawal induced anxiety in light & dark test at 24 h post-nicotine withdrawal time on pre-treatment centrally (i.c.v) with histaminergic agents like histamine (0.1, 50 μg/mouse), histamine H₃ receptor inverse agonist, thioperamide (2, 10 μg/mouse), histamine H₁ receptor agonist, FMPH (2, 6.5 μg/mouse) or H₂ receptor agonist amthamine (0.1, 0.5 μg/mouse) or intraperitoneally (i.p.) with histamine precursor, l-histidine (250, 500 mg/kg) as compared to control nicotine withdrawn animals. Furthermore, mice pre-treated with all these histaminergic agents except histamine H₁ receptor agonist, FMPH shows exacerbated expression to post-nicotine withdrawal induced total abstinence (somatic) score in mice. On the other hand, central injection of selective histamine H₁ receptor antagonist, cetirizine (0.1 μg/mouse, i.c.v.) or H₂ receptor antagonist, ranitidine (50 μg/mouse, i.c.v) to mice 10 min before 24 h post-nicotine withdrawal time completely alleviated the expression of nicotine withdrawal induced anxiety and somatic behavior. Thus, it can be contemplated that the blockade of central histamine H₁ or H₂ receptor during the nicotine withdrawal phase could be a novel approach to mitigate the nicotine withdrawal associated anxiety-like manifestations. Contribution of endogenous histamine via H₁ or H₂ receptor stimulation in the nicotine withdrawal induced anxiety and somatic behavior is proposed.

2017-07-01·Biochemical and biophysical research communications3区 · 生物学

JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice

3区 · 生物学

Article

作者: Nakamura, Tadaho ; Iida, Tomomitsu ; Mogi, Asuka ; Kárpáti, Anikó ; Matsuzawa, Takuro ; Yoshikawa, Takeo ; Naganuma, Fumito ; Yanai, Kazuhiko ; Harada, Ryuichi ; Kitano, Haruna

Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl-_d-aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis.

项与 H3 receptor inverse agonists( Arena Pharmaceuticals, Inc.) 相关的新闻（医药）

2024-10-23

·Endpoints

Alto Neuroscience's mid-stage trial misses primary endpoint in depression

Alto Neuroscience’s stock tumbled 60% on Wednesday morning, the day after the company said a mid-stage trial for its oral small molecule failed to improve symptoms of major depressive disorder. In the Phase 2b trial, which the company described as a first-of-its-kind precision biomarker-based study in psychiatry, ALTO-100 didn’t show improvement over placebo in a change from baseline using the Montgomery-Åsberg Depression Rating Scale (MADRS) in 301 patients at the end of the six-week treatment period. The trial also didn’t hit “key” secondary endpoints that included efficacy versus placebo in MDD as measured using the Clinician Global Impression Scale-severity — a tool used to measure the severity of illness — and remission rates based on MADRS. Alto said the safety and tolerability profile was “favorable” and consistent with previous data. In a Phase 2a study last year, ALTO-100 hit the primary endpoint, with the treatment showing a greater improvement in both the monotherapy and adjunctive treatment groups. “We will move quickly to evaluate the full data set to better understand these findings and incorporate learnings from this large data set across our platform,” Alto CEO Amit Etkin said in a statement , adding that the company expects “our strong cash balance to support us through multiple near-term clinical milestones across our pipeline.” Alto $ANRO went public earlier this year, bringing in $129 million in February, above its original plans to raise $89 million. In its latest financial filing in August, the Eli Lilly-backed startup said it expects its existing cash to provide runway into 2027. ALTO-100 is still being investigated as an adjunctive treatment in a Phase 2b study in bipolar depression. Alto also has several upcoming data readouts for other assets that are expected next year. This includes ALTO-203, an H3 receptor inverse agonist, and ALTO-300 — both in major depressive disorder. In a note on Wednesday, TD Cowen analysts said they were disappointed by the newest slate of data but still “optimistic” about the drug. “We suspect the enrichment signal may have been seen in the adjunct MDD population,” TD Cowen’s Ritu Baral wrote. “Without additional detail on the Ph2b data, we hesitate to extend read-through to the rest of ANRO’s pipeline of agents paired with distinct biomarkers.” Others on Wall Street were more concerned. Jefferies analysts told investors they think the “study’s failure is driven by a lack of drug effect rather than [management] execution error” and that Tuesday’s data “raises questions around ANRO’s overall biomarker approach to CNS/psychiatry.”

临床2期临床结果临床失败

100 项与 H3 receptor inverse agonists( Arena Pharmaceuticals, Inc.) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
认知障碍	临床前	美国	Arena Pharmaceuticals, Inc.	2009-09-24
入睡和睡眠障碍	临床前	美国	Arena Pharmaceuticals, Inc.	2009-09-24
嗜睡	临床前	美国	Arena Pharmaceuticals, Inc.	2009-09-24