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

Johannes Levin, Nand Sing, Sue Melbourne, Amber Morgan, Carla Mariner, Maria Grazia Spillantini, Michal Wegrzynowicz, Jeffrey W Dalley, Simon Langer, Sergey Ryazanov, Andrei Leonov, Christian Griesinger, Felix Schmidt, Daniel Weckbecker, Kai Prager, Torsten Matthias, Armin Giese, Johannes Levin, Nand Sing, Sue Melbourne, Amber Morgan, Carla Mariner, Maria Grazia Spillantini, Michal Wegrzynowicz, Jeffrey W Dalley, Simon Langer, Sergey Ryazanov, Andrei Leonov, Christian Griesinger, Felix Schmidt, Daniel Weckbecker, Kai Prager, Torsten Matthias, Armin Giese

Abstract

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: 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.

Keywords: Anle138b; Disease modification; Multiple system atrophy; Parkinson disease; Protein aggregation; α-synuclein.

Conflict of interest statement

Johannes Levin reports part-time employment by MODAG GmbH and a grant of the Michael J Fox Foundation for Parkinson´s Research. In addition, he reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, all outside the submitted work. He is beneficiary of the phantom share program of MODAG GmbH. In addition, he is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH.

Nand Sing reports employment by Quotient Sciences which was contracted under a services agreement to perform activities related to the design, conduct, and reporting of this clinical study.

Sue Melbourne reports employment by Quotient Sciences which was contracted under a services agreement to perform activities related to the design, conduct, and reporting of this clinical study.

Amber Morgan reports employment by Quotient Sciences which was contracted under a services agreement to perform activities related to the design, conduct, and reporting of this clinical study.

Carla Mariner reports employment by Quotient Sciences which was contracted under a services agreement to perform activities related to the design, conduct, and reporting of this clinical study.

Maria Grazia Spillantini reports funding for this study from Parkinson´s UK consulting fees from Mission therapeutics and speaker fees from CASMA and BIAL, outside this work. She is in the Scientific Advisory Board of the Tau consortium sponsored by the Rainwater foundation.

Michal Wegrzynowicz reports no conflicts of interest.

Jeffrey Dalley reports grants held with Glaxo Smith Kline and Boehringer Ingelheim Pharma GmbH & Co. KG.

Simon Langer reports no conflicts of interest.

Sergey Ryazanov reports part-time employment by MODAG GmbH. In addition, he is inventor in a patent “water-soluble derivatives of 3,5-diphelyl-diazole compounds” (PCT EP 16/081084 etc.) licensed to MODAG GmbH, and a patent “new drugs for inhibiting aggregation of proteins involved in disease linked to protein aggregation and/or neurodegenerative diseases” (EP 2307381 etc.), which includes the compound anle138b, licensed to MODAG GmbH and a patent PCT/EP2020/082778 “Novel compounds for the diagnosis, treatment and prevention of disease associated with the aggregation of alpha-synuclein”. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Andrei Leonov reports part-time employment by MODAG GmbH. In addition, he is inventor in a patent “water-soluble derivatives of 3,5-diphelyl-diazole compounds” (PCT EP 16/081084 etc.) licensed to MODAG GmbH, and a patent “new drugs for inhibiting aggregation of proteins involved in disease linked to protein aggregation and/or neurodegenerative diseases” (EP 2307381 etc.), which includes the compound anle138b, licensed to MODAG GmbH and a patent PCT/EP2020/082778 “Novel compounds for the diagnosis, treatment and prevention of disease associated with the aggregation of alpha-synuclein”. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Christian Griesinger reports consultancy for and being a shareholder of MODAG GmbH. In addition, he is inventor in a patent “water-soluble derivatives of 3,5-diphelyl-diazole compounds” (PCT EP 16/081084 etc.) licensed to MODAG GmbH, and a patent “new drugs for inhibiting aggregation of proteins involved in disease linked to protein aggregation and/or neurodegenerative diseases” (EP 2307381 etc.), which includes the compound anle138b, licensed to MODAG GmbH and a patent PCT/EP2020/082778 “Novel compounds for the diagnosis, treatment and prevention of disease associated with the aggregation of alpha-synuclein”.

Felix Schmidt reports employment by MODAG GmbH. In addition, he is inventor in a patent “water-soluble derivatives of 3,5-diphelyl-diazole compounds” (PCT EP 16/081084 etc.) and is inventor in a patent “Novel Compounds for the Diagnosis, Treatment and Prevention of Diseases Associated with the Aggregation of alpha-Synuclein” (PCT/EP2020/082778) both licensed to MODAG GmbH. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Daniel Weckbecker reports employment by MODAG GmbH. In addition, he is inventor in a patent “Novel Compounds for the Diagnosis, Treatment and Prevention of Diseases Associated with the Aggregation of alpha-Synuclein” (PCT/EP2020/082778) licensed to MODAG GmbH. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Kai Prager reports part-time employment by MODAG GmbH. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Torsten Matthias reports being CEO of MODAG GmbH and being a shareholder of MODAG GmbH. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Armin Giese reports employment by and being a shareholder of MODAG GmbH. In addition, he is inventor in a patent “water-soluble derivatives of 3,5-diphelyl-diazole compounds” (PCT EP 16/081084 etc.) licensed to MODAG GmbH, and a patent “new drugs for inhibiting aggregation of proteins involved in disease linked to protein aggregation and/or neurodegenerative diseases” (EP 2307381 etc.), which includes the compound anle138b, licensed to MODAG GmbH and a patent PCT/EP2020/082778 “Novel compounds for the diagnosis, treatment and prevention of disease associated with the aggregation of alpha-synuclein” and he is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH. In addition, he is beneficiary of the phantom share program of MODAG GmbH.

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile: SAD: Single ascending dose. Dosing groups: 8 placebo participants & 6 participants per dose level verum (50, 100, 200, 300 mg). MAD: Multiple ascending dose. Dosing groups: 6 placebo participants & 6 participants per dose level verum (100, 200, 300 mg). FES: Food effect study. Groups: 6 participants each randomized to sequences. Sequence A: 150 mg fed → 150 mg fasted· Sequence B: 150 mg fasted → 150 mg fed.
Figure 2
Figure 2
Pharmakokinetic profile of anle138b: Geometric Mean (CV%) of anle138b in healthy volunteers. a) Data from day 7 of multiple oral administration of anle138b in capsule form from N=6 participants per dosis group are shown. b) Data following single oral administration of anle138b in capsule form from N=12 participants in the fed or in the fasted state, respectively, are shown.

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Source: PubMed

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