A Randomized, Double-blind, Placebo Controlled, Dose Ranging Study to Assess the Safety, Tolerability, and Efficacy of HTL0018318 in Patients With Dementia With Lewy Bodies

To establish the safety and efficacy of HTL0018318 compared with placebo when administered once daily for 12 weeks to patients with dementia with Lewy bodies.

开始日期2019-07-01

申办/合作机构

Nxera Pharma UK Ltd.

[+1]

NCT03456349 / Completed临床1期

A Phase 1b Randomized, Double-blind, Placebo-controlled, Parallel Group, Multi-center Study to Determine the Safety and Tolerability of HTL0018318 in Subjects With Alzheimer's Disease Receiving Standard-of-care

Multi-centre study of HTL0018318 in patients with Alzheimer's disease as an add-on to standard-of-care

开始日期2017-11-10

申办/合作机构

Nxera Pharma UK Ltd.

[+1]

NCT03198624 / Completed临床1期

A Two-part, Single and Multiple Dose, Parallel Group Study to Assess Safety and Pharmacokinetics of Oral HTL0018318 in Healthy Japanese and Caucasian Subjects

This is a single and multiple dose, parallel group study to assess safety and pharmacokinetics of oral HTL0018318 in healthy Japanese and Caucasian subjects.

开始日期2017-05-16

申办/合作机构

Nxera Pharma UK Ltd.

100 项与 HTL-18318 相关的临床结果

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100 项与 HTL-18318 相关的转化医学

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100 项与 HTL-18318 相关的专利（医药）

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项与 HTL-18318 相关的文献（医药）

2022-01-01·Alzheimer's & dementia (New York, N. Y.)

A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M₁ receptor agonist HTL0018318 in patients with mild‐to‐moderate Alzheimer's disease

Article

作者: Weir, Malcolm Peter ; Jones, Stephen Paul ; Congreve, Miles ; Godwood, Alex ; Dewit, Odile ; Maruff, Paul T. ; Liptrot, Janet ; Bakker, Geor ; Tasker, Tim ; Light, Gregory A. ; Cross, David M. ; Nathan, Pradeep J. ; Ruparelia, Bharat ; Brown, Alastair J.H. ; Millais, S. Babli

Abstract:

Introduction:

This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild‐to‐moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.

Methods:

A randomized, double‐blind, placebo‐controlled 4‐week safety study of HTL0018318 with up‐titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.

Results:

Treatment‐emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7–21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post‐dose, HTL0018318‐related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up‐titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints.

Discussion:

HTL0018318 was well tolerated in mild‐to‐moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.

2021-12-01·Alzheimer's research & therapy2区 · 医学

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study

2区 · 医学

ArticleOA

作者: Cross, David M ; Liptrot, Jan ; Doll, Robert Jan ; Brown, Alastair ; Tasker, Tim ; Congreve, Miles ; Hart, Ellen P ; Groeneveld, Geert Jan ; Marshall, Fiona H ; Brown, Giles A ; Weir, Malcolm ; Nathan, Pradeep J ; Klaassen, Erica S ; Bakker, Charlotte

Abstract:

Background:

The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia’s including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.

Methods:

This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15–35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.

Results:

HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15–35 mg. Maximum plasma concentrations were achieved after 1–2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.

Conclusion:

Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB.

Trial registration:

Netherlands Trial Register identifier NTR5781. Registered on 22 March 2016.

2021-09-01·Drugs in R&D4区 · 医学

Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

4区 · 医学

ArticleOA

作者: Labots, Geert ; Tasker, Tim ; Liptrot, Jan ; Dickinson, Steve ; Groeneveld, Geert Jan ; van der Aart, Jasper ; Cross, David M ; Klaassen, Erica S ; Bakker, Charlotte

INTRODUCTION:

HTL0018318 is a selective muscarinic M₁ receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil).

OBJECTIVE:

We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil.

METHODS:

This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics.

RESULTS:

AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics.

CONCLUSION:

HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil.

CLINICAL TRIAL REGISTRATION:

Netherlands Trial register identifier NL5915, registered on 28 October 2016.

项与 HTL-18318 相关的新闻（医药）

2021-01-08

·BioSpace

AbbVie Says Goodbye to Sosei's Neurological-Focused Muscarinic Agonist Programs

Smith Collection/Gado/Getty Images Sosei Group Corporation has announced it is regaining the worldwide rights to its muscarinic agonist programs after AbbVie said it is backing away from the program. Allergan, which was recently absorbed by AbbVie, previously penned the licensing pack with Sosei’s muscarinic agonist programs back in 2016. The partnership with Allergan also came after the company walked away from another $160 million merger, instead agreeing to a $3.3 billion licensing deal for worldwide rights to a neurological disorders drug portfolio from Sosei subsidiary Heptares. Allergen agreed to give Heptares an uprfront payment of $125 as well as $665 million in milestone payments and up to $2.5 billion in milestones related to sales of the developed products. Muscarinic agonists have been developed to treat various cognitive challenges associated with dementia and neurobehavioral issues. In 2018, Allergan and Sosei voluntarily halted a clinical trial of one of its selective small molecule muscarinic M1 receptor agonist, HTL0018318, which was being developed for Alzheimer’s disease (AD) and other dementias. The trial was suspended because of safety concerns observed in a non-human primates. At the time, the drug had been investigated in a total of 310 human participants across the U.S. and Europe, including health people and patients with mild-to-moderate AD. In 2019, Sosei made the decision to stop development of the compound. "We are delighted to regain rights to this portfolio of novel subtype-selective muscarinic receptor agonists (M4, M1 and dual M1/M4 agonists), including several clinical and preclinical candidates with substantial data associated,” said Shinichi Tamura, Chairman, President and CEO of Sosei Heptares. “We enjoyed a productive relationship with Allergan over the course of our muscarinic agonist collaboration and continue to work positively with AbbVie on a new program in inflammatory diseases that we announced in June last year.” Tamura added that the “considerable progress” made between the Sosei/Allergan partnership has reinforced Sosei’s “view in the potential of this approach to create important new products that treat severe and debilitating symptoms of Alzheimer's disease, schizophrenia and other neurological diseases.” "In addition, the R&D collaboration has generated a diverse pipeline of next-generation, selective muscarinic agonists with novel chemistry that have benefitted from insights gained in clinical trials and from advanced drug design technologies,” Tamura said. “These new and differentiated candidates exhibit highly attractive properties for further development.” Tamura noted that Sosei is currently developing and looking for a new partner for the program. The news coincides with the company’s announcement of its full-year results, which is planned for some time in February 2021. According to Sosei, the retainment of the worldwide rights to its muscarinic agonist programs will have “no immediate impact on the consolidated financial results of the accounting period ending December 2021.” Back in June, Sosei Haptares and AbbVie announced a discovery collaboration and licensing partnership, which is seeking to develop and commercialize novel treatments modulating G protein-coupled receptor targets for inflammatory and autoimmune diseases. AbbVie agreed to pay Sosei an upfront and near-term milestone payments of $32 million. Possible milestones of up to $377 million and tiered royalties on global commercial sales were also inked into the deal. The partnership allows AbbVie to expand the collaboration to up to four targets. Featured Jobs on BioSpace

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2021-01-05

·BioSpace

Sosei Heptares to Regain Worldwide Rights to Muscarinic Agonist Programs

TOKYO and CAMBRIDGE, England, Jan. 5, 2021 /PRNewswire/ -- Sosei Group Corporation ("the Company") (TSE: 4565) announces it is to regain the worldwide rights to its muscarinic agonist programs. The program was licensed to Allergan in April 2016, and Allergan was acquired by AbbVie in May 2020. This decision to return worldwide rights was based on business decisions regarding AbbVie's pipeline strategy and not on any efficacy, safety or other data related to the collaboration programs. As a result of this process, AbbVie has notified Sosei Heptares that it will be returning to Sosei Heptares all assets in development under the program, together with all associated intellectual property licensed by Sosei Heptares to Allergan, and all clinical and preclinical data generated under the partnership. Sosei Heptares will now conduct a full internal review to determine a strategy for the further development and re-partnering of the program. The outcome of this review is expected to be reported around the time of the Company's full year results presentation in February 2021. The event reported today has no immediate impact on the consolidated financial results for the accounting period ending December 2021. Should any impacts or other matters that require an announcement be identified, the Company will announce such matters promptly. Shinichi Tamura, Chairman, President and CEO of Sosei Heptares, commented: "We are delighted to regain rights to this portfolio of novel subtype-selective muscarinic receptor agonists (M 4 , M 1 and dual M 1 /M 4 agonists), including several clinical and preclinical candidates with substantial data associated. We enjoyed a productive relationship with Allergan over the course of our muscarinic agonist collaboration and continue to work positively with AbbVie on a new program in inflammatory diseases that we announced in June last year. "The considerable progress that we made together with Allergan has reinforced our view in the potential of this approach to create important new products that treat severe and debilitating symptoms of Alzheimer's disease, schizophrenia and other neurological diseases. We are also encouraged by the growing industry interest and validation of this novel approach to treating these diseases. "In addition, the R&D collaboration has generated a diverse pipeline of next-generation, selective muscarinic agonists with novel chemistry that have benefitted from insights gained in clinical trials and from advanced drug design technologies. These new and differentiated candidates exhibit highly attractive properties for further development. "The value of the selective M 1 agonists was enhanced with a signal observed in early clinical trials of HTL0018318, and in addition we have been advancing the development of such agonists with novel chemistry. We will decide which selective M 1 agonist program to prioritise after further study. "We are excited by this opportunity and look forward to disclosing our strategy for the further development and re-partnering of this program at around the time of our full year results in February 2021." About the License Agreement Sosei Heptares and Allergan entered a global R&D and commercialization partnership in April 2016 under which Allergan licensed exclusive global rights to a broad portfolio of novel subtype-selective muscarinic receptor agonists (M 4 , M 1 and dual M 1 /M 4 agonists) in development for the treatment of major neurological disorders, including Alzheimer's disease. Effective 4 January 2021, the License Agreement is terminated. All intellectual property rights pertaining to the muscarinic program licensed to Allergan and subsequently added to through the collaboration, and all preclinical and clinical data, will be regained by Sosei Heptares. About Muscarinic Receptors Muscarinic receptors are G protein-coupled receptors (GPCRs) found in multiple tissues including the brain, cardiovascular system and gastrointestinal tract. Selective activation of M 4 and M 1 receptors in the brain is a clinically validated approach to treating cognitive and neuropsychological symptoms of neurological diseases, including Schizophrenia, Alzheimer's disease, Parkinson's disease and others. Until now, attempts to develop medicines that selectively target M 4 and M 1 receptors have been unsuccessful because of side effects caused by the activation of M 2 and M 3 receptors. Highly selective M 4 or M 1 agonists that do not activate M 2 or M 3 therefore are highly sought after and expected to have the potential to address major unmet medical needs with blockbuster potential. About Sosei Heptares We are an international biopharmaceutical group focused on the discovery and early development of new medicines originating from our proprietary GPCR-targeted StaR® technology and structure-based drug design platform capabilities. We are advancing a broad and deep pipeline of novel medicines across multiple therapeutic areas, including neurology, immunology, gastroenterology and inflammatory diseases. We have established partnerships with some of the world's leading pharmaceutical companies, including AbbVie, AstraZeneca, Biohaven, Genentech (Roche), GSK, Novartis, Pfizer and Takeda and additionally with multiple emerging technology companies. Sosei Heptares is headquartered in Tokyo, Japan with corporate and R&D facilities in Cambridge, UK. "Sosei Heptares" is the corporate brand and trademark of Sosei Group Corporation, which is listed on the Tokyo Stock Exchange (ticker: 4565). Sosei, Heptares, the logo and StaR® are trademarks of Sosei Group companies. For more information, please visit . LinkedIn: @soseiheptaresco | Twitter: @soseiheptaresco | YouTube: @soseiheptaresco Enquiries: Sosei Heptares – Media and Investor Relations Hironoshin Nomura, SVP Investor Relations and Corporate Strategy +81 (0)3 6679 2178 | Hironoshin.Nomura@SoseiHeptares.com Shinichiro Nishishita, VP Investor Relations, Head of Regulatory Disclosures +81 (0)3 5210 3399 | IR@SoseiHeptares.com Citigate Dewe Rogerson Yas Fukuda – Japanese Media +81 (0)3 4360 9234 | Yas.Fukuda@citigatedewerogerson.com Mark Swallow, David Dible – International Media +44 (0)20 7638 9571 | SoseiHeptares@citigatedewerogerson.com Forward-looking statements This press release contains forward-looking statements, including statements about the discovery, development and commercialization of products. Various risks may cause Sosei Group Corporation's actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialize products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialization activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. View original content: SOURCE Sosei Heptares Company Codes: Berlin:JSS, OTC-PINK:SOLTF, Tokyo:4565, Frankfurt:JSS, Munich:JSS, Stuttgart:JSS

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100 项与 HTL-18318 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
痴呆	临床2期	-	Allergan Ltd. (Ireland)	-
痴呆	临床2期	-	Nxera Pharma UK Ltd.	-
阿尔茨海默症	临床1期	捷克	Nxera Pharma UK Ltd.	2017-11-10
阿尔茨海默症	临床1期	捷克	Allergan Ltd. (Ireland)	2017-11-10
阿尔茨海默症	临床1期	波兰	Nxera Pharma UK Ltd.	2017-11-10
阿尔茨海默症	临床1期	波兰	Allergan Ltd. (Ireland)	2017-11-10
阿尔茨海默症	临床1期	斯洛伐克	Nxera Pharma UK Ltd.	2017-11-10
阿尔茨海默症	临床1期	斯洛伐克	Allergan Ltd. (Ireland)	2017-11-10
阿尔茨海默症	临床1期	西班牙	Allergan Ltd. (Ireland)	2017-11-10
阿尔茨海默症	临床1期	西班牙	Nxera Pharma UK Ltd.	2017-11-10