Overview

Name: Emrusolmin
Synonyms: Anle138b, TEV-56286
Chemical Name: 3-(1,3-Benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline), alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Parkinson's Disease (Phase 1/2), Multiple System Atrophy (Phase 2)
Company: MODAG GmbH, Teva

Background

Anle138b is an oral, brain-penetrant, general inhibitor of protein aggregation. It was identified in a high-throughput screen for small-molecule inhibitors of α-synuclein and prion protein oligomerization. The compound is being developed for treatment of the rapidly progressing synucleinopathy multiple-system atrophy (MSA) and for Parkinson's disease (PD). It could potentially be applied to other synucleinopathies, such as dementia with Lewy bodies (DLB).

This diphenyl pyrazole compound has been shown to suppress oligomer formation in vitro and in vivo. It inhibited pathogenic protein accumulation and neurodegeneration, and improved survival in mouse models of α-synuclein and prion disease (Apr 2011 conference news; Wagner et al., 2013; Vallabh et al., 2023).

Structural studies revealed that anle138b binding to α-synuclein fibrils involves stable polar interactions inside the tubular fibril cavity, and placed the small molecule's central pyrazole moiety near α-synuclein's protein backbone (Antonschmidt et al., 2022; Dervişoğlu et al., 2023).

In α-synuclein transgenic mouse models of PD, anle138b administration reduced protein deposition in brain and improved dopamine neuron function and movement, even when treatment began after symptoms developed (Wegrzynowicz et al., 2019; Mar 2015 conference news; Levin et al., 2014).

In a mouse model of MSA created by overexpressing human α-synuclein in oligodendrocytes, anle138b reduced α-synuclein oligomers, preserved dopaminergic neurons, and improved walking compared with nontreated controls (Heras-Garvin et al., 2019). In a model mimicking more severe MSA, anle138b slightly improved motor skills, but did not significantly change neurodegeneration or α-synuclein accumulation in glia in mice expressing α-synuclein and exposed to a mitochondrial toxin (Fellner et al., 2016).

Anle138b was also effective in mouse models of tau pathology, where treatment of young mice decreased neuron loss, increased survival, and improved cognition (Aug 2014 conference news; Wagner et al., 2015). Even in older tau mice with established pathology, the compound was able to lessen tau deposition and reverse metabolic decline (Brendel et al., 2019). It inhibited tau aggregation in cell culture models, as well (Dominguez-Meijide et al., 2020). Bioinformatics analyses proposed testable mechanisms of action for anle138b (Kondratyev et al., 2022; Hosseini-Gerami et al., 2023).

In the APP/PS1Δ9 mouse model of Aβ pathology, anle138b restored hippocampal synaptic plasticity and memory (Martinez Hernandez et al., 2018). A study comparing anle138b to the investigational α-synuclein immunotherapy Affitope PD03 reported that both improved PD-related outcomes such as α-syn oligomer levels, microglial activation, neurodegeneration in the substantia nigra, and gait (Lemos et al., 2020).

A PET tracer based on anle138b is in development (Kuebler et al., 2020; Orlovskaya et al., 2023).

Findings

In December 2019, MODAG began a Phase 1, first-in-human study of the safety, tolerability, and blood levels of orally administered anle138b in healthy adults. Held in Nottingham, U.K., the trial enrolled 68 volunteers, who received single ascending doses of 50 mg and higher, or multiple ascending doses for seven days, or matching placebo. Primary outcomes were adverse events, changes in clinical lab measures, electrocardiogram, vital signs, and physical exam. Secondary outcomes were blood concentrations of drug. An optional third study arm measured the effect of food on pharmacokinetics. The trial finished in August 2020. According to a company press release, doses up to 300 mg daily produced no side effects. The drug's half-life was 12 hours, and plasma levels significantly exceeded those required for efficacy in animal models. Uptake was not affected by food. Results were published after peer review (Levin et al., 2022).

In December 2020, the company began a Phase 1b study in 48 people with Parkinson’s disease, also in Nottingham. The trial assessed safety, tolerability, and pharmacokinetics of 150 mg and higher daily doses for seven days. Other endpoints included CSF drug levels and changes in motor function. The U.K. study was supported by the Michael J. Fox Foundation. It concluded in December 2022 after enrolling 70 participants. No results have been released.

In October 2021, MODAG and TEVA Pharmaceuticals announced their collaboration to develop anle138b for Parkinson’s disease and multiple systems atrophy (press release).

From September 2022 to February 2023, the companies conducted a drug-drug interaction study with the CYP1A2 and CYP3A4 probes, caffeine, midazolam, and fluvoxamine.

MODAG and TEVA plan to begin a Phase 2 efficacy study in late 2024, according to a presentation at the March AD/PD conference in Lisbon (Apr 2024 conference news). Called TOPAS-MSA, the study aims to enroll 160 people diagnosed clinically with possible or probable MSA, who are able to walk at least 30 feet unassisted, and are on stable medication. Participants will be randomized to 300 mg emrusolmin or placebo once daily for one year, against a primary endpoint of progression in a modified unified MSA rating scale (UMSARS) part I score. Secondary endpoints are safety and tolerability. A one-year, open-label extension is planned. The study will run in the U.S., France, Italy, Germany, Spain, Israel, and Japan. This trial does not appear in registries yet.

For details on anle138b trials, see clinicaltrials.gov.

Last Updated: 02 May 2024

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References

News Citations

Research Models Citations

Paper Citations

Levin J, Sing N, Melbourne S, Morgan A, Mariner C, Spillantini MG, Wegrzynowicz M, Dalley JW, Langer S, Ryazanov S, Leonov A, Griesinger C, Schmidt F, Weckbecker D, Prager K, Matthias T, Giese A. 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. Epub 2022 Apr 29 PubMed.
Wagner J, Ryazanov S, Leonov A, Levin J, Shi S, Schmidt F, Prix C, Pan-Montojo F, Bertsch U, Mitteregger-Kretzschmar G, Geissen M, Eiden M, Leidel F, Hirschberger T, Deeg AA, Krauth JJ, Zinth W, Tavan P, Pilger J, Zweckstetter M, Frank T, Bähr M, Weishaupt JH, Uhr M, Urlaub H, Teichmann U, Samwer M, Bötzel K, Groschup M, Kretzschmar H, Griesinger C, Giese A. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease. Acta Neuropathol. 2013 Jun;125(6):795-813. PubMed.
Vallabh SM, Zou D, Pitstick R, O'Moore J, Peters J, Silvius D, Kriz J, Jackson WS, Carlson GA, Minikel EV, Cabin DE. Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease. J Virol. 2023 Feb 28;97(2):e0167222. Epub 2023 Jan 18 PubMed.
Antonschmidt L, Matthes D, Dervişoğlu R, Frieg B, Dienemann C, Leonov A, Nimerovsky E, Sant V, Ryazanov S, Giese A, Schröder GF, Becker S, de Groot BL, Griesinger C, Andreas LB. The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils. Nat Commun. 2022 Sep 14;13(1):5385. PubMed.
Dervişoğlu R, Antonschmidt L, Nimerovsky E, Sant V, Kim M, Ryazanov S, Leonov A, Fuentes-Monteverde JC, Wegstroth M, Giller K, Mathies G, Giese A, Becker S, Griesinger C, Andreas LB. Anle138b interaction in α-synuclein aggregates by dynamic nuclear polarization NMR. Methods. 2023 Jun;214:18-27. Epub 2023 Apr 8 PubMed.
Wegrzynowicz M, Bar-On D, Calo' L, Anichtchik O, Iovino M, Xia J, Ryazanov S, Leonov A, Giese A, Dalley JW, Griesinger C, Ashery U, Spillantini MG. Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model. Acta Neuropathol. 2019 Oct;138(4):575-595. Epub 2019 May 31 PubMed.
Levin J, Schmidt F, Boehm C, Prix C, Bötzel K, Ryazanov S, Leonov A, Griesinger C, Giese A. The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathol. 2014 Mar 11; PubMed.
Heras-Garvin A, Weckbecker D, Ryazanov S, Leonov A, Griesinger C, Giese A, Wenning GK, Stefanova N. Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy. Mov Disord. 2019 Feb;34(2):255-263. Epub 2018 Nov 19 PubMed.
Fellner L, Kuzdas-Wood D, Levin J, Ryazanov S, Leonov A, Griesinger C, Giese A, Wenning GK, Stefanova N. Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy. Front Neurosci. 2016;10:99. Epub 2016 Mar 10 PubMed.
Wagner J, Krauss S, Shi S, Ryazanov S, Steffen J, Miklitz C, Leonov A, Kleinknecht A, Göricke B, Weishaupt JH, Weckbecker D, Reiner AM, Zinth W, Levin J, Ehninger D, Remy S, Kretzschmar HA, Griesinger C, Giese A, Fuhrmann M. Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathol. 2015 Nov;130(5):619-31. Epub 2015 Oct 6 PubMed.
Brendel M, Deussing M, Blume T, Kaiser L, Probst F, Overhoff F, Peters F, von Ungern-Sternberg B, Ryazanov S, Leonov A, Griesinger C, Zwergal A, Levin J, Bartenstein P, Yakushev I, Cumming P, Boening G, Ziegler S, Herms J, Giese A, Rominger A. Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. Alzheimers Res Ther. 2019 Aug 1;11(1):67. PubMed.
Dominguez-Meijide A, Vasili E, König A, Cima-Omori MS, Ibáñez de Opakua A, Leonov A, Ryazanov S, Zweckstetter M, Griesinger C, Outeiro TF. Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization. Sci Rep. 2020 Jul 30;10(1):12827. PubMed.
Kondratyev MS, Rudnev VR, Nikolsky KS, Petrovsky DV, Kulikova LI, Malsagova KA, Stepanov AA, Kopylov AT, Kaysheva AL. In Silico Study of the Interactions of Anle138b Isomer, an Inhibitor of Amyloid Aggregation, with Partner Proteins. Int J Mol Sci. 2022 Dec 17;23(24) PubMed.
Hosseini-Gerami L, Ficulle E, Humphryes-Kirilov N, Airey DC, Scherschel J, Kananathan S, Eastwood BJ, Bose S, Collier DA, Laing E, Evans D, Broughton H, Bender A. Mechanism of action deconvolution of the small-molecule pathological tau aggregation inhibitor Anle138b. Alzheimers Res Ther. 2023 Mar 14;15(1):52. PubMed.
Martinez Hernandez A, Urbanke H, Gillman AL, Lee J, Ryazanov S, Agbemenyah HY, Benito E, Jain G, Kaurani L, Grigorian G, Leonov A, Rezaei-Ghaleh N, Wilken P, Arce FT, Wagner J, Fuhrman M, Caruana M, Camilleri A, Vassallo N, Zweckstetter M, Benz R, Giese A, Schneider A, Korte M, Lal R, Griesinger C, Eichele G, Fischer A. The diphenylpyrazole compound anle138b blocks Aβ channels and rescues disease phenotypes in a mouse model for amyloid pathology. EMBO Mol Med. 2018 Jan;10(1):32-47. PubMed.
Lemos M, Venezia S, Refolo V, Heras-Garvin A, Schmidhuber S, Giese A, Leonov A, Ryazanov S, Griesinger C, Galabova G, Staffler G, Wenning GK, Stefanova N. Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance. Transl Neurodegener. 2020 Sep 24;9(1):38. PubMed.
Kuebler L, Buss S, Leonov A, Ryazanov S, Schmidt F, Maurer A, Weckbecker D, Landau AM, Lillethorup TP, Bleher D, Saw RS, Pichler BJ, Griesinger C, Giese A, Herfert K. [11C]MODAG-001-towards a PET tracer targeting α-synuclein aggregates. Eur J Nucl Med Mol Imaging. 2021 Jun;48(6):1759-1772. Epub 2020 Dec 28 PubMed.
Orlovskaya VV, Fedorova OS, Viktorov NB, Vaulina DD, Krasikova RN. One-Pot Radiosynthesis of [18F]Anle138b-5-(3-Bromophenyl)-3-(6-[18F]fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazole-A Potential PET Radiotracer Targeting α-Synuclein Aggregates. Molecules. 2023 Mar 17;28(6) PubMed.

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