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

Xiong, Chengjie; Sing, Nand; Melbourne, Sue; Morgan, Amber; Mariner, Carla; Spillantini, Maria Grazia; Węgrzynowicz, Michał; Dalley, Jeffrey W.; Langer, Simon; Ryazanov, Sergey; Leonov, Andrei; Griesinger, Christian; Schmidt, Felix; Weckbecker, Daniel; Prager, Kai; Tenbusch, Matthias; Giese, Armin

doi:10.1016/j.ebiom.2022.104021

Cited by 36 publications

(29 citation statements)

References 26 publications

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“…Nevertheless, it can be stated that genetic variations underlying monogenic forms of PD can be identified more often in early-onset cases [3]. To date, the number of genetically confirmed genes and loci causing PD in monogenic form is thirteen (PARK1, −2, −6-10, − [12][13][14][15][16][17]. Furthermore, four, so far unconfirmed, PARK loci are known as well (PARK3, −5, −11, −18) [4].…”

Section: Introductionmentioning

confidence: 99%

The genetic background of Parkinson’s disease and novel therapeutic targets

Salamon

Zádori

Szpisjak

et al. 2022

Expert Opinion on Therapeutic Targets

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Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The median age of disease onset is around 60 years. From a genetic point of view, PD is basically considered a sporadic, idiopathic disease, however, hereditary components can be detected in 5-10% of patients. Expanding data are available regarding the targeted molecular therapy of the disease. Areas covered: The aim of this current review article is to provide brief clinical and molecular insight into three important genetic forms (LRRK2, SNCA, GBA) of hereditary PD subtypes and to present the human clinical trials in relation to these forms of the disease. Expert opinion: These small hereditary subgroups are crucially important in drug development, because the general trend is that clinical trials that treat PD patients as a large group, without any separation, do not meet expectations. As a result, no long term conclusions can currently be drawn regarding the effectiveness of the molecules tested in these phase 1 and 2 studies. Further precise studies are needed in the near future.

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Section: Introductionmentioning

confidence: 99%

The genetic background of Parkinson’s disease and novel therapeutic targets

Salamon

Zádori

Szpisjak

et al. 2022

Expert Opinion on Therapeutic Targets

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“…However, the agents used exhibit certain limitations, including degradation by proteases and inefficient crossing of the blood–brain barrier (BBB). Oligomerization inhibitors targeting α-Syn have been widely investigated [ 101 , 102 , 103 , 104 ]. For instance, the small molecule UCB0599 (Neuropore Therapies, Inc.) has been shown to cross the BBB with low toxicity in control subjects; it has performed successfully in phase I clinical trials [ 105 ].…”

Section: α-Syn Protein Aggregates and Aggregate Inhibitorsmentioning

confidence: 99%

Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

et al. 2022

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Neurodegenerative diseases (NDs) commonly present misfolded and aggregated proteins. Considerable research has been performed to unearth the molecular processes underpinning this pathological aggregation and develop therapeutic strategies targeting NDs. Fibrillary deposits of α-synuclein (α-Syn), a highly conserved and thermostable protein, are a critical feature in the development of NDs such as Alzheimer’s disease (AD), Lewy body disease (LBD), Parkinson’s disease (PD), and multiple system atrophy (MSA). Inhibition of α-Syn aggregation can thus serve as a potential approach for therapeutic intervention. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality, gaining the hotspot in pharmaceutical research. Additionally, interest is growing in the use of food-derived bioactive compounds as intervention agents against NDs via functional foods and dietary supplements. According to reports, dietary bioactive phospholipids may have cognition-enhancing and neuroprotective effects, owing to their abilities to influence cognition and mental health in vivo and in vitro. However, the mechanisms by which lipids may prevent the pathological aggregation of α-Syn warrant further clarification. Here, we review evidence for the potential mechanisms underlying this effect, with a particular focus on how porcine liver decomposition product (PLDP)-derived lysophospholipids (LPLs) may inhibit α-Syn aggregation.

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“…Anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1 H -pyrazole] shows efficacy in animal models for several aggregation related diseases 8 , 10 – 14 . It was tested successfully in healthy volunteers 15 and is currently undergoing phase Ib testing in Parkinson’s disease (NCT04685265). On a molecular level, anle138b was shown to interfere with α-synuclein oligomerization in vitro, inhibiting pore formation in membranes as well as cytochrome c leakage from mitochondria and depopulating α-synuclein aggregates in vivo 8 , 14 .…”

Section: Introductionmentioning

confidence: 99%

The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils

Antonschmidt

Matthes²,

Dervişoğlu

et al. 2022

Nat Commun

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Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.

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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

Cited by 36 publications

References 26 publications

The genetic background of Parkinson’s disease and novel therapeutic targets

The genetic background of Parkinson’s disease and novel therapeutic targets

Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils

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