Show simple item record

dc.contributor.authorLevin, Johannes
dc.contributor.authorSing, Nand
dc.contributor.authorMelbourne, Sue
dc.contributor.authorMorgan, Amber
dc.contributor.authorMariner, Carla
dc.contributor.authorSpillantini, Maria
dc.contributor.authorWegrzynowicz, Michal
dc.contributor.authorDalley, Jeffrey
dc.contributor.authorLanger, Simon
dc.contributor.authorRyazanov, Sergey
dc.contributor.authorLeonov, Andrei
dc.contributor.authorGriesinger, Christian
dc.contributor.authorSchmidt, Felix
dc.contributor.authorWeckbecker, Daniel
dc.contributor.authorPrager, Kai
dc.contributor.authorMatthias, Torsten
dc.contributor.authorGiese, Armin
dc.date.accessioned2022-06-07T08:15:41Z
dc.date.available2022-06-07T08:15:41Z
dc.date.issued2022-06
dc.identifier.issn2352-3964
dc.identifier.other35500536
dc.identifier.otherPMC9065877
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337811
dc.description.abstractBACKGROUND: 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: 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: gov-identifier: NCT04208152. EudraCT-number: 2019-004218-33. FINDINGS: Between December 17th, 2019 and June 27th, 2020 196 healthy volunteers were screened and 68 participants were enrolled. Of these, all completed the study per protocol. There were no major protocol deviations. Adverse events in this healthy volunteer trial were mostly mild and all fully recovered or resolved prior to discharge. From baseline to completion of the trial no medically significant individual changes were observed in any system organ class. Already at multiple doses of 200 mg, exposure levels above the fully effective exposure in the MI2 mouse Parkinson model were observed. INTERPRETATION: 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: This study was funded by MODAG GmbH and by the Michael J. Fox foundation for Parkinson's Research.
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101647039
dc.sourceessn: 2352-3964
dc.subjectParkinson disease
dc.subjectProtein aggregation
dc.subjectα-synuclein
dc.subjectMultiple System Atrophy
dc.subjectDisease Modification
dc.subjectAnle138b
dc.titleSafety, 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.
dc.typeArticle
dc.date.updated2022-06-07T08:15:40Z
prism.publicationNameEBioMedicine
prism.volume80
dc.identifier.doi10.17863/CAM.85220
dcterms.dateAccepted2022-04-08
rioxxterms.versionofrecord10.1016/j.ebiom.2022.104021
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSpillantini, Maria [0000-0002-8544-7332]
dc.contributor.orcidDalley, Jeffrey [0000-0002-2282-3660]
dc.identifier.eissn2352-3964


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International