Objective: The objective of the TOPAS-MSA study is to assess the safety and efficacy of emrusolmin (anle138b/TEV-56286), an orally bioavailable small molecule targeting aggregated α-synuclein, in treating Multiple System Atrophy (MSA) over a 56-week, multi-center, randomized, double-blind, placebo-controlled phase 2 trial.

Background: MSA is characterized by deposition of misfolded and aggregated α-synuclein. Emrusolmin, targets aggregated α-synuclein species and shows strong disease-modifying effects in animal models^1-3. The TOPAS-MSA study aims to explore safety and efficacy of emrusolmin and seeks to address the critical unmet medical need in MSA treatment by offering a therapy to potentially slow or halt the rapid progression.

Method: To evaluate the safety and efficacy of 300 mg emrusolmin once daily, a 56-week, multi-center, randomized, double-blind, 2-arm, placebo-controlled (1:1) phase 2 study will be performed. Inclusion criteria include “clinically possible” or “clinically probable” MSA according to the second consensus criteria (2008 Gilman)⁴ and the ability to ambulate at least 10 meters without the assistance of another person. Patient stratification includes type of MSA (MSA-C or MSA-P). The primary endpoints are safety and tolerability as well as change in a modified unified MSA rating scale (UMSARS) part I.  An open-label extension to the Phase 2 study is planned to provide additional safety and efficacy data beyond 1 year of treatment.

Results: A phase 1 program including a first-in-human study in healthy volunteers (NCT04208152) and a first-in-patient study (NCT04685265) generated safety and tolerability data of emrusolmin dosed up to 28 days. Exposure (AUC) in these studies was comparable to levels showing therapeutic activity in animal models. This provides the basis for long-term studies, with an enrolment target of 80 patients per group.

Conclusion: There is a significant unmet medical need for MSA treatment as there are no therapies to address the underlying pathology of neurodegeneration. Thus, TOPAS-MSA will test emrusolmin as treatment for MSA.

This abstract was previously presented as an oral presentation at AD/PD 24 on 8th March 2024. This work has not been published.

References: References:
1) Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathol. 2013;125(6):795-813.
2) Levin J, Schmidt F, Boehm C, Prix C, Botzel K, Ryazanov S, et al. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014;127(5):779-80.
3) Wegrzynowicz M, Bar-On D, Calo L, Anichtchik O, Iovino M, Xia J, et al. Depopulation of dense alpha-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathol. 2019;138(4):575-95.
4) Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Dürr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008 Aug 26;71(9):670-6.
5) Levin J, Sing N, Melbourne S, Morgan A, Mariner C, et al. 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. EBioMedicine. 2022 Jun;80:104021.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/topas-msa-targeting-oligomer-pathology-of-alpha-synuclein-a-study-evaluating-the-safety-and-efficacy-of-emrusolmin-in-patients-with-multiple-system-atrophy/