In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease
Abstract Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-pen...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00552-7 |
| _version_ | 1797259420212658176 |
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| author | Diana L. Price Asma Khan Rachel Angers Alvaro Cardenas Maria Key Prato Massimo Bani Douglas W. Bonhaus Martin Citron Anja-Leona Biere |
| author_facet | Diana L. Price Asma Khan Rachel Angers Alvaro Cardenas Maria Key Prato Massimo Bani Douglas W. Bonhaus Martin Citron Anja-Leona Biere |
| author_sort | Diana L. Price |
| collection | DOAJ |
| description | Abstract Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265). |
| first_indexed | 2024-03-09T05:30:10Z |
| format | Article |
| id | doaj.art-528ea93e40cf43c7b16378bd59b03e20 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-04-24T23:09:08Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-528ea93e40cf43c7b16378bd59b03e202024-03-17T12:19:24ZengNature Portfolionpj Parkinson's Disease2373-80572023-07-019111210.1038/s41531-023-00552-7In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s diseaseDiana L. Price0Asma Khan1Rachel Angers2Alvaro Cardenas3Maria Key Prato4Massimo Bani5Douglas W. Bonhaus6Martin Citron7Anja-Leona Biere8Neuropore Therapies, Inc.Neuropore Therapies, Inc.UCB Biopharma SPRLUCB Biopharma SPRLUCB Biopharma SPRLUCB Biopharma SPRLNeuropore Therapies, Inc.UCB Biopharma SPRLUCB Biopharma SPRLAbstract Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).https://doi.org/10.1038/s41531-023-00552-7 |
| spellingShingle | Diana L. Price Asma Khan Rachel Angers Alvaro Cardenas Maria Key Prato Massimo Bani Douglas W. Bonhaus Martin Citron Anja-Leona Biere In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease npj Parkinson's Disease |
| title | In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease |
| title_full | In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease |
| title_fullStr | In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease |
| title_full_unstemmed | In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease |
| title_short | In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease |
| title_sort | in vivo effects of the alpha synuclein misfolding inhibitor minzasolmin supports clinical development in parkinson s disease |
| url | https://doi.org/10.1038/s41531-023-00552-7 |
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