emrusolmin (TEV- '286) / MODAG, Teva - LARVOL DELTA

A Study to Assess New Formulations of TEV-56286 (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Teva Branded Pharmaceutical Products R&D LLC

New P1 trial

OPTIMIZING SPECIFICITY OF PET TRACERS FOR PROTEIN AGGREGATES: A MULTILEVEL APPROACH FROM IN VITRO SCREENING TO IN VIVO VALIDATION (ADPD 2025) - "This study presents a multi -tiered compound screening workflow, de signed to improve the diagnostic precision of novel PET tracers and validate target engagement for clinical drug candidates, such as emrusolmin... This preclinical tracer development workflow allowed us to confirm the target engagement of the drug candidate in clinical trials, highlighting its potential for diagnosing synucleinopathies and evaluating alpha -synu clein-targeted therapies using PET. This approach will ultimately advance the precision and effectiveness of NDD diagnostics and treatments."

Preclinical • CNS Disorders

EMRUSOLMIN A NOVEL Α-SYNUCLEIN TARGETING DRUG, IS EFFICACIOUS IN IN VITRO MODELS OF MULTIPLE SYSTEMS ATROPHY (ADPD 2025) - "These results demonstrate that emrusolmin inhibits α-syn aggregation in MSA in vitro models and that it does so in clinically relevant concentrations. Thus, these findings provide a foundation for further testing of emrusolmin's poten tial as a disease modifying agent in MSA patients."

Preclinical • CNS Disorders • Movement Disorders • Multiple System Atrophy • Parkinson's Disease • Solid Tumor

UPDATE ON TOPAS-MSA: AN ON-GOING PHASE 2 STUDY FOLLOWED BY AN OPEN-LABEL-EXTENSION STUDY OF EMRUSOLMIN IN MULTIPLE SYSTEM ATROPHY (ADPD 2025) - "Currently there are no therapies to slow or stop the rapid progression of neurodegeneration and associated disability. TOPAS-MSA will provide data on the treatment potential of emrusolmin for MSA with the OLE offering further long-term data."

Clinical • P2 data • CNS Disorders • Movement Disorders • Multiple System Atrophy

Slightly viscous oxidized alginate dispersions as vehicles for intranasal administration of the α-synuclein aggregation inhibitor Anle 138b in free form or encapsulated in solid lipid nanoparticles. (PubMed, Int J Pharm) - "Drug release studies employing SVDs and SNF/mucin mixture as release medium showed quantitative release of the inhibitor within 48 h. We conclude that Anle 138b SLN Alg OX/HPMC SVD constitutes a promising formulation due to its capability to provide the inhibitor in quantitative and sustained way, being not cytotoxic towards human RPMI 2650 cells and neuronal SH-SY5Y cells."

Journal

Mass Balance Clinical Trial With TEV-56286 (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. | Active, not recruiting ➔ Completed

Trial completion

Targeting Protein Misfolding and Aggregation as a Therapeutic Perspective in Neurodegenerative Disorders. (PubMed, Int J Mol Sci) - "The most recent research focuses on finding potential applications targeting the pathological forms of proteins responsible for neurodegeneration. This review highlights the mechanisms relevant to protein-dependent neurodegeneration based on the most common disorders and describes current therapeutic approaches targeting protein misfolding and aggregation."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Lewy Body Disease • Movement Disorders • Multiple System Atrophy • Parkinson's Disease • Progressive Supranuclear Palsy • Solid Tumor

Mass Balance Clinical Trial With TEV-56286 (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. | Not yet recruiting ➔ Active, not recruiting

Enrollment closed

Mass Balance Clinical Trial With TEV-56286 (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

New P1 trial

TOPAS-MSA: Targeting Oligomer Pathology of Alpha-Synuclein – A Study Evaluating the Safety and Efficacy of Emrusolmin in Patients with Multiple System Atrophy (MDS Congress 2024) - P1 | "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."

Clinical • CNS Disorders • Multiple System Atrophy

TOPAS-MSA: A Study to Test if TEV-56286 is Effective in Relieving Multiple System Atrophy Safety and Efficacy Study (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

New P2 trial • CNS Disorders • Movement Disorders • Multiple System Atrophy

Interfering with aggregated α-synuclein in advanced melanoma leads to a major upregulation of MHC class II proteins. (PubMed, Melanoma Res) - "We also performed proteomic and transcriptomic studies of human melanoma xenografts that were treated systemically with the anle138b compound. The results reveal that interfering with oligomerized α-synuclein in the melanoma cells in these tumor xenografts led to a substantial upregulation and expression of major histocompatibility complex proteins, which are pertinent to enhancing anti-melanoma immune responses."

Journal • Metastases • CNS Disorders • Genetic Disorders • Melanoma • Movement Disorders • Oncology • Parkinson's Disease • Skin Cancer • Solid Tumor

Development of Positron Emission Tomography Agent for Alpha-Synuclein Imaging (SNMMI 2024) - "Our group identified several alpha-synuclein ligands with a better ADME profile than anle138b by in silico approach... A series of novel ligands based on the structure-activity relationship of carbazole, imidazolopyridine and imidazolopyrimidine were designed, and in silico docking studies were performed to obtain binding affinity of novel alpha-synuclein ligands. Based on ADME and in vitro assays, the lead ligand [11C]ASRN37 was radiolabeled and exhbited higher BBB penetration in mice."

Alzheimer's Disease • Anesthesia • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Movement Disorders • Multiple System Atrophy • Parkinson's Disease

Molecular docking analysis of α-Synuclein aggregation with Anle138b. (PubMed, Bioinformation) - "Protein-protein docking showed that Anle138b interferes with α-synuclein decamer formation. These results highlight the oligomer-directed inhibitory mechanism of Anle138b, without hindering the monomeric forms and provide molecular insights to advance its therapeutic development for Parkinson's and related synucleinopathies."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease. (PubMed, PLoS Pathog) - "None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent."

Journal • CNS Disorders • Insomnia • Sleep Disorder

TOPAS-MSA: TARGETING OLIGOMER PATHOLOGY OF ALPHA-SYNUCLEIN - A STUDY EVALUATING THE SAFETY AND EFFICACY OF EMRUSOLMIN IN PATIENTS WITH MULTIPLE SYSTEM ATROPHY (ADPD 2024) - P1 | "There is a significant unmet medical need for MSA as there are no therapies to either slow, stop, or reverse the rapid progression of neurodegeneration. Thus, TOPAS-MSA will test Emrusolmin as treatment for MSA."

Clinical • CNS Disorders • Movement Disorders • Multiple System Atrophy

[11C]MODAG 005: TOWARDS A NOVEL PET TRACER TARGETING PATHOLOGICAL ALPHA-SYNUCLEIN AGGREGATES IN THE BRAIN (ADPD 2024) - "Such a PET tracer could allow to monitor disease progression and measure the effects of novel disease-modifying therapeutics targeting alpha-synuclein pathology. We conducted a systematic PET tracer development program starting from the therapeutic lead compound emrusolmin (anle138b), which binds to pathologically aggregated alpha-synuclein and for which a binding site on alpha-synuclein fibrils has recently been elucidated with atomic resolution. We have developed MODAG-005, which meets all key criteria for an alpha-synuclein PET tracer... MODAG-005 is a promising alpha-synuclein PET tracer candidate. The available preclinical data supports testing in a first-in-human study."

CNS Disorders • Movement Disorders • Multiple System Atrophy • Parkinson's Disease

ADVANCING TRACER DEVELOPMENT FOR ALPHA-SYNUCLEIN PATHOLOGY: VALIDATION ON NATIVE BRAIN TARGETS (ADPD 2024) - "Saturation binding assays were conducted using several PET candidates (derivatives of anle138b) to determine the target density (Bmax) and radioligand affinity (Kd)... This revised (micro)autoradiography approach is a powerful tool for compound screenings in synuclein tracer development, providing significant advantage by allowing tracer binding to unmodified, native targets, delivering exceptional spatial resolution, and offering insights into spatial distribution. This technique is indispensable for discerning specific binding, determining Bmax and Kd values, and excluding off-target interactions, thereby ensuring the development of specific tracers."

CNS Disorders

Insights into the management of Lewy body dementia: a scoping review. (PubMed, Ann Med Surg (Lond)) - "Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated...Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out...With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Discovery of small molecule benzothiazole and indole derivatives tackling tau 2N4R and α-synuclein fibrils. (PubMed, Bioorg Med Chem) - "Here, we rationally designed and synthesized benzothiazole- and indole-based compounds using the structural hybridization strategy between the benzothiazole N744 cyanine dye and the diphenyl pyrazole Anle138b that showed anti-aggregation activity towards 2N4R tau and α-syn, respectively...Moreover, compound 48 remarkably inhibited α-syn inclusion and cell confluence using M17D cells. Collectively, compounds 46 and 48 could serve as a basic structure for further optimization to develop clinically active AD and PD disease-modifying agents."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform. (PubMed, Autophagy) - "In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates...An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • Progressive Supranuclear Palsy • Proteinopathy • Targeted Protein Degradation • SQSTM1

Anle138b-P1-02: A randomised, double-blinded, placebo-controlled phase 1b study to investigate safety, tolerability, pharmacokinetics and pharmacodynamics of the oligomer modulator anle138b (MDS Congress 2023) - P1 | "In patients with PD across a wide range of disease severity, anle138b was safe and well tolerated when administered 7-28 days. Exposures were reached above the minimally effective plasma levels seen in animal models. Efficacy trials in patients with synucleinopathies are planned."

Clinical • P1 data • PK/PD data • CNS Disorders • Multiple System Atrophy • Parkinson's Disease

Lewy Body Dementia: An Overview of Promising Therapeutics. (PubMed, Curr Neurol Neurosci Rep) - "We review 11 prospective disease-modifying therapies (DMT) including four with phase 2 data (neflamapimod, nilotinib, bosutinib, and E2027); four with some limited data in symptomatic populations including phase 1, open-label, registry, or cohort data (vodabatinib, ambroxol, clenbuterol, and terazosin); and three with phase 1 data in healthy populations (Anle138b, fosgonimeton, and CT1812). We also appraise four symptomatic therapies for cognitive impairment, but due to safety and efficacy concerns, only NYX-458 remains under active investigation. Of symptomatic therapies for psychosis recently investigated, pimavanserin shows promise in LBD, but studies of nelotanserin have been suspended. Although the discovery of novel symptomatic and disease-modifying therapeutics remains a significant challenge, recently published and upcoming trials signify promising strides toward that aim."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease • Psychiatry

Probing the molecular mechanisms of α-synuclein inhibitors unveils promising natural candidates through machine-learning QSAR, pharmacophore modeling, and molecular dynamics simulations. (PubMed, Mol Divers) - "Finally, molecular dynamics simulations demonstrated the superior stability of LTS0078917 compared to the clinical candidate, Anle138b...Our dynamic analysis of the inhibitor-monomer complex revealed a tendency towards a more compact conformation, potentially reducing the likelihood of adopting an elongated structure that favors the formation and aggregation of pathological oligomers. These findings offer valuable insights for the development of novel α-synuclein inhibitors derived from natural sources."

Journal • Machine learning • CNS Disorders • Movement Disorders • Parkinson's Disease

Endogenous Amyloid-formed Ca-permeable Channels in Aged 3xTg AD Mice. (PubMed, Function (Oxf)) - "Here, we report an unexpected finding of the spontaneous Ca oscillations in aged 3xTg AD mice but not in age-matched wild-type mice. These spontaneous Ca oscillations are sensitive to extracellular Ca, ZnCl, and the Aβ channel blocker Anle138b, suggesting that these spontaneous Ca oscillations in aged 3xTg AD mice are mediated by endogenous Aβ-formed channels."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • APP