Safety, tolerability and pharmacokinetics of the oligomer modulator anle138b with exposure levels sufficient for therapeutic efficacy in a murine Parkinson model: A randomised, double-blind, placebo-controlled phase 1a trial.
Anle138b
Disease modification
Multiple system atrophy
Parkinson disease
Protein aggregation
α-synuclein
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jun 2022
Jun 2022
Historique:
received:
17
09
2021
revised:
08
04
2022
accepted:
08
04
2022
pubmed:
3
5
2022
medline:
15
6
2022
entrez:
2
5
2022
Statut:
ppublish
Résumé
Synucleinopathies such as Parkinson ́s disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) are characterized by deposition of misfolded and aggregated α-synuclein. Small aggregates (oligomers) of α-synuclein have been shown to be the most relevant neurotoxic species and are targeted by anle138b, an orally bioavailable small molecule compound which shows strong disease-modifying effects in animal models of synucleinopathies. Anle138b was studied in a single-centre, double-blind, randomised, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects. Eligible participants were randomly assigned (1:1 for sentinel subjects and 1:5 for main group) to placebo or anle138b (dose range 50 mg to 300 mg per day), respectively. In addition, the effect of food on the pharmakokinetics of anle138b in healthy subjects was examined in doses of 150 mg per day. Participants were randomized to treatment sequence (fed→fasted) or (fasted→fed). Treatment was administered orally in hard gelatine capsules containing either 10 mg or 30 mg of anle138b or excipient only. The primary endpoints were safety and tolerability, the secondary endpoint was pharmakokinetics. Data from all randomized individuals were evaluated. gov-identifier: NCT04208152. EudraCT-number: 2019-004218-33. Between December 17 The favourable safety and PK profile of anle138b in doses resulting in exposures above the fully effective plasma level in a mouse Parkinson model warrant further clinical trials in patients with synucleinopathies. This study was funded by MODAG GmbH and by the Michael J. Fox foundation for Parkinson's Research.
Sections du résumé
BACKGROUND
BACKGROUND
Synucleinopathies such as Parkinson ́s disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) are characterized by deposition of misfolded and aggregated α-synuclein. Small aggregates (oligomers) of α-synuclein have been shown to be the most relevant neurotoxic species and are targeted by anle138b, an orally bioavailable small molecule compound which shows strong disease-modifying effects in animal models of synucleinopathies.
METHODS
METHODS
Anle138b was studied in a single-centre, double-blind, randomised, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy subjects. Eligible participants were randomly assigned (1:1 for sentinel subjects and 1:5 for main group) to placebo or anle138b (dose range 50 mg to 300 mg per day), respectively. In addition, the effect of food on the pharmakokinetics of anle138b in healthy subjects was examined in doses of 150 mg per day. Participants were randomized to treatment sequence (fed→fasted) or (fasted→fed). Treatment was administered orally in hard gelatine capsules containing either 10 mg or 30 mg of anle138b or excipient only. The primary endpoints were safety and tolerability, the secondary endpoint was pharmakokinetics. Data from all randomized individuals were evaluated.
CLINICALTRIALS
RESULTS
gov-identifier: NCT04208152. EudraCT-number: 2019-004218-33.
FINDINGS
RESULTS
Between December 17
INTERPRETATION
CONCLUSIONS
The favourable safety and PK profile of anle138b in doses resulting in exposures above the fully effective plasma level in a mouse Parkinson model warrant further clinical trials in patients with synucleinopathies.
FUNDING
BACKGROUND
This study was funded by MODAG GmbH and by the Michael J. Fox foundation for Parkinson's Research.
Identifiants
pubmed: 35500536
pii: S2352-3964(22)00205-5
doi: 10.1016/j.ebiom.2022.104021
pmc: PMC9065877
pii:
doi:
Substances chimiques
3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
0
Benzodioxoles
0
Pyrazoles
0
alpha-Synuclein
0
Banques de données
ClinicalTrials.gov
['NCT04208152']
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
104021Subventions
Organisme : Parkinson's UK
ID : G-0701
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1102
Pays : United Kingdom
Organisme : Parkinson's UK
ID : G-1703
Pays : United Kingdom
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
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