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
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‐contro...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/trc2.12273 |
| _version_ | 1826950808663490560 |
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| author | Pradeep J. Nathan S. Babli Millais Alex Godwood Odile Dewit David M. Cross Janet Liptrot Bharat Ruparelia Stephen Paul Jones Geor Bakker Paul T. Maruff Gregory A. Light Alastair J.H. Brown Malcolm Peter Weir Miles Congreve Tim Tasker |
| author_facet | Pradeep J. Nathan S. Babli Millais Alex Godwood Odile Dewit David M. Cross Janet Liptrot Bharat Ruparelia Stephen Paul Jones Geor Bakker Paul T. Maruff Gregory A. Light Alastair J.H. Brown Malcolm Peter Weir Miles Congreve Tim Tasker |
| author_sort | Pradeep J. Nathan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T21:53:46Z |
| format | Article |
| id | doaj.art-d2ea8035b82442a48e018eec2348acbe |
| institution | Directory Open Access Journal |
| issn | 2352-8737 |
| language | English |
| last_indexed | 2025-02-17T22:37:38Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj.art-d2ea8035b82442a48e018eec2348acbe2024-12-03T12:37:31ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372022-01-0181n/an/a10.1002/trc2.12273A 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 diseasePradeep J. Nathan0S. Babli Millais1Alex Godwood2Odile Dewit3David M. Cross4Janet Liptrot5Bharat Ruparelia6Stephen Paul Jones7Geor Bakker8Paul T. Maruff9Gregory A. Light10Alastair J.H. Brown11Malcolm Peter Weir12Miles Congreve13Tim Tasker14Heptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKCross Pharma Consulting Limited Cambridge UKHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKtranScrip Partners LLP Wokingham UKHeptares Therapeutics Ltd Cambridge UKCogstate Ltd New Haven Connecticut USADepartment of Psychiatry University of San Diego San Diego California USAHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKHeptares Therapeutics Ltd Cambridge UKAbstract 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.https://doi.org/10.1002/trc2.12273Alzheimer's diseaseattentioncholinergicclinical trialcognitionCogstate neuropsychological test battery |
| spellingShingle | Pradeep J. Nathan S. Babli Millais Alex Godwood Odile Dewit David M. Cross Janet Liptrot Bharat Ruparelia Stephen Paul Jones Geor Bakker Paul T. Maruff Gregory A. Light Alastair J.H. Brown Malcolm Peter Weir Miles Congreve Tim Tasker 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 Alzheimer’s & Dementia: Translational Research & Clinical Interventions Alzheimer's disease attention cholinergic clinical trial cognition Cogstate neuropsychological test battery |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Alzheimer's disease attention cholinergic clinical trial cognition Cogstate neuropsychological test battery |
| url | https://doi.org/10.1002/trc2.12273 |
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