1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, College of Medicine, Rochester, MN, USA
2Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, USA
3Department of Psychiatry and Psychology, Mayo Clinic, College of Medicine, Rochester, MN, USA
4Department of Neuroscience Program, Mayo Clinic, College of Medicine, Rochester, MN, USA
Copyright © 2021 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Conflicts of Interest
D.S.C. is a scientific advisory board member for Peptron Inc. Peptron had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. All the other authors declare no biomedical financial interests or potential conflicts of interest.
Funding Statement
This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, and National Institute on Alcohol Abuse and Alcoholism (K01 AA027773 to SK; R01 AA018779, R01 AA029258, and R01 AG072898 to DSC).
Author Contributions
Conceptualization: Pei Shang, Doo-Sup Choi. Funding acquisition: Doo-Sup Choi. Investigation: all authors. Project administration: Pei Shang, Doo-Sup Choi. Resources: Pei Shang, Matthew Baker, Samantha Banks, Doo-Sup Choi. Supervision: Doo-Sup Choi. Writing—original draft: all authors. Writing—review & editing: all authors.
Medication | Trial design | Subjects | Treatment doses | Outcomes | Reference |
---|---|---|---|---|---|
Istradefylline | A phase 2, 12-week, double-blind, placebo-controlled study of istradefylline in PD patients on L-DOPA/carbidopa | 790 PD patients with an average OFF time at least 2 h/day and approximately 3.2 years after diagnosis | 20 (for 163 subjects) or 60 mg (for 155 subjects) per day | Significant reduction in the awake time per day spent in OFF state | [119] |
Istradefylline | A phase 3, multicenter, open-label, long-term (52 w) study of istradefylline in PD patients experiencing wearing-off | 313 PD patients approximately 7.5 years after onset and 3.3 years after showing motor complications | 20 mg as starting dosage with/o adjustment to 40 mg | Significant OFF time reduction since the 2nd week | [120] |
Istradefylline | Istradefylline as adjunctive treatment to levodopa for 12 weeks in a phase 3, double-blind manner in PD patients with motor complications | 373 PD patients 3.3 years after showing motor complications | 20 or 40 mg per day | Istradefylline markedly reduced daily OFF time and was well-tolerated in patients with motor complications | [121] |
Istradefylline | A phase 3 randomized, 12-week, double-blind, placebo-controlled parallel-group study of istradefylline with different doses in patients on levodopa therapy | 610 PD patients with an average OFF time at least 3 h/day. 9 years after diagnosis, and 3.6 years after motor fluctuations | 10, 20, and 40 mg per day | Istradefylline did not impact daily OFF time but significantly improved motor scores at 40 mg per day | [122] |
Tozadenant | A phase 2, double-blind, randomized, placebo-controlled study of the safety and efficacy of SYN115 as adjunctive therapy in L-DOPA- treated PD subjects | 337 PD patients with an average OFF time at least 6 h/day and 8.7 years after diagnosis | 60 or 120 or 180 or 240 mg/BID | Tozadenant significantly reduced daily OFF time and improved motor signs without increasing dyskinesia | [123] |
Preladenant | A phase 2, 36-week, open-label, follow-up safety study of SCH420814 in subjects with PD | 140 PD patients with moderate to severe PD > 5 years | 5 mg/BID | Long-term preladenant treatment are well-tolerated and sustained the OFF time reduction | [124] |
GLP1R agonist | PD models | Treatment details | Experimental results | Reference |
---|---|---|---|---|
Ex-4 | 6-OHDA/LPS-treated rat model | Ex-4 (0.1 and 0.5 µg/kg) was given 7 days after the intracerebral toxin injection, BID for 7 days | Circling behavior was attenuated in Ex-4 group; striatal tissue dopamine level increased in Ex-4 group | [125] |
Ex-4 | 6-OHDA-treated rat model | Ex-4 (0.1 μg/kg) was given 5 weeks after the intracerebral toxin injection, BID for 21 days | Ex-4 promoted neurogenesis and normalized the imbalance in dopamine levels; Ex-4 also increased the dopaminergic neurons in substantia nigra | [111] |
Ex-4 | MPTP-treated mouse model | Ex-4 (20 nM, 0.25 μL/h) was given 7 days 2 hour before MPTP treatment via left ventricle administration | Ex-4 protected dopaminergic neurons, preserved dopamine levels and improved motor functions | [97] |
Extended-release Ex-4 (PT302) | 6-OHDA-treated rat model | Ex-4 (0.4 or 2 mg/kg) was given every 2 weeks for 10 weeks starting 16 days before the unilateral lesion induced by 6-OHDA | PT302 increased tyrosine hydroxylase levels in the lesioned substantia nigra and striatum; PT302 reduced the neurodegeneration of nigrostriatal dopaminergic neurons | [126] |
Lixisenatide | MPTP-treated mouse model | Lixisenatide (10 nmol/kg) was given after the 7-day MPTP treatment, once a day for 14 days | Lixisenatide prevented MPTP-induced motor impairment, reduction in tyrosine hydroxylase levels in substantia nigra, and reduction in pro-apoptotic signaling | [127] |
GLP1R agonist | Treatment details | Subjects | Study design | Primary outcome measures | Conclusions | Reference |
---|---|---|---|---|---|---|
Ex-4 | Self-administer twice-daily subcutaneous injections of 5 µg for 1 month and 10 µg for 11 months | 45 patients: moderate PD approximately 7.5 years since disease onset | Single-blind, placebo-controlled. 21-Ex-4 and 24-placebo | MDS-UPDRS and nonmotor tests at baseline, 6 months, 12 months, and 14 months | MDS-UPDRS scores in the Ex-4 treated group improved 2.7 points compared with 2.2 in the control group; motor and cognitive functions also improved in Ex-4 treated group | [108] |
Ex-4 | Once-weekly subcutaneous injections of 2 mg for 48 weeks | 62 patients: moderate PD with DAergic treatment with wearing-off effects | Single-center, randomized, double-blind, placebo-controlled. 32-Ex-4 and 30-placebo. | MDS-UPDRS motor subscale (part 3) | Ex-4 significantly improved MDS-UPDRS scores of patients in the OFF time | [98] |
Ex-4 | 2 mg of once weekly or placebo for 48 weeks followed by a 12-week washout period | 60 patients: moderate PD; patients were receiving dopaminergic treatment | Single-center, randomized, double-blind, placebo-controlled. 31-Ex-4 and 29-placebo | MDS-UPDRS and serum were collected after 12-week withdrawal; insulin and PKB-related pathways were tested | Ex-4 treated group showed increased phospho-IRS1 and elevated expression of total AKT and phospho-mTOR; improvement of MDS-UPDRS was correlated to total and phospho-mTOR level | [113] |
Ex-4: exenatide-4, mTOR: mechanistic target of rapamycin, IRS1: insulin receptor substrate 1, MDS-UPDRS: Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale, PD: Parkinson’s disease, PKB: protein kinase B, DAergic: dopaminergic, GLP1R: glucagon-like peptide-1 receptor.
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Medication | Trial design | Subjects | Treatment doses | Outcomes | Reference |
---|---|---|---|---|---|
Istradefylline | A phase 2, 12-week, double-blind, placebo-controlled study of istradefylline in PD patients on L-DOPA/carbidopa | 790 PD patients with an average OFF time at least 2 h/day and approximately 3.2 years after diagnosis | 20 (for 163 subjects) or 60 mg (for 155 subjects) per day | Significant reduction in the awake time per day spent in OFF state | [119] |
Istradefylline | A phase 3, multicenter, open-label, long-term (52 w) study of istradefylline in PD patients experiencing wearing-off | 313 PD patients approximately 7.5 years after onset and 3.3 years after showing motor complications | 20 mg as starting dosage with/o adjustment to 40 mg | Significant OFF time reduction since the 2nd week | [120] |
Istradefylline | Istradefylline as adjunctive treatment to levodopa for 12 weeks in a phase 3, double-blind manner in PD patients with motor complications | 373 PD patients 3.3 years after showing motor complications | 20 or 40 mg per day | Istradefylline markedly reduced daily OFF time and was well-tolerated in patients with motor complications | [121] |
Istradefylline | A phase 3 randomized, 12-week, double-blind, placebo-controlled parallel-group study of istradefylline with different doses in patients on levodopa therapy | 610 PD patients with an average OFF time at least 3 h/day. 9 years after diagnosis, and 3.6 years after motor fluctuations | 10, 20, and 40 mg per day | Istradefylline did not impact daily OFF time but significantly improved motor scores at 40 mg per day | [122] |
Tozadenant | A phase 2, double-blind, randomized, placebo-controlled study of the safety and efficacy of SYN115 as adjunctive therapy in L-DOPA- treated PD subjects | 337 PD patients with an average OFF time at least 6 h/day and 8.7 years after diagnosis | 60 or 120 or 180 or 240 mg/BID | Tozadenant significantly reduced daily OFF time and improved motor signs without increasing dyskinesia | [123] |
Preladenant | A phase 2, 36-week, open-label, follow-up safety study of SCH420814 in subjects with PD | 140 PD patients with moderate to severe PD > 5 years | 5 mg/BID | Long-term preladenant treatment are well-tolerated and sustained the OFF time reduction | [124] |
GLP1R agonist | PD models | Treatment details | Experimental results | Reference |
---|---|---|---|---|
Ex-4 | 6-OHDA/LPS-treated rat model | Ex-4 (0.1 and 0.5 µg/kg) was given 7 days after the intracerebral toxin injection, BID for 7 days | Circling behavior was attenuated in Ex-4 group; striatal tissue dopamine level increased in Ex-4 group | [125] |
Ex-4 | 6-OHDA-treated rat model | Ex-4 (0.1 μg/kg) was given 5 weeks after the intracerebral toxin injection, BID for 21 days | Ex-4 promoted neurogenesis and normalized the imbalance in dopamine levels; Ex-4 also increased the dopaminergic neurons in substantia nigra | [111] |
Ex-4 | MPTP-treated mouse model | Ex-4 (20 nM, 0.25 μL/h) was given 7 days 2 hour before MPTP treatment via left ventricle administration | Ex-4 protected dopaminergic neurons, preserved dopamine levels and improved motor functions | [97] |
Extended-release Ex-4 (PT302) | 6-OHDA-treated rat model | Ex-4 (0.4 or 2 mg/kg) was given every 2 weeks for 10 weeks starting 16 days before the unilateral lesion induced by 6-OHDA | PT302 increased tyrosine hydroxylase levels in the lesioned substantia nigra and striatum; PT302 reduced the neurodegeneration of nigrostriatal dopaminergic neurons | [126] |
Lixisenatide | MPTP-treated mouse model | Lixisenatide (10 nmol/kg) was given after the 7-day MPTP treatment, once a day for 14 days | Lixisenatide prevented MPTP-induced motor impairment, reduction in tyrosine hydroxylase levels in substantia nigra, and reduction in pro-apoptotic signaling | [127] |
GLP1R agonist | Treatment details | Subjects | Study design | Primary outcome measures | Conclusions | Reference |
---|---|---|---|---|---|---|
Ex-4 | Self-administer twice-daily subcutaneous injections of 5 µg for 1 month and 10 µg for 11 months | 45 patients: moderate PD approximately 7.5 years since disease onset | Single-blind, placebo-controlled. 21-Ex-4 and 24-placebo | MDS-UPDRS and nonmotor tests at baseline, 6 months, 12 months, and 14 months | MDS-UPDRS scores in the Ex-4 treated group improved 2.7 points compared with 2.2 in the control group; motor and cognitive functions also improved in Ex-4 treated group | [108] |
Ex-4 | Once-weekly subcutaneous injections of 2 mg for 48 weeks | 62 patients: moderate PD with DAergic treatment with wearing-off effects | Single-center, randomized, double-blind, placebo-controlled. 32-Ex-4 and 30-placebo. | MDS-UPDRS motor subscale (part 3) | Ex-4 significantly improved MDS-UPDRS scores of patients in the OFF time | [98] |
Ex-4 | 2 mg of once weekly or placebo for 48 weeks followed by a 12-week washout period | 60 patients: moderate PD; patients were receiving dopaminergic treatment | Single-center, randomized, double-blind, placebo-controlled. 31-Ex-4 and 29-placebo | MDS-UPDRS and serum were collected after 12-week withdrawal; insulin and PKB-related pathways were tested | Ex-4 treated group showed increased phospho-IRS1 and elevated expression of total AKT and phospho-mTOR; improvement of MDS-UPDRS was correlated to total and phospho-mTOR level | [113] |
A2AR: adenosine A2A receptor, BID: twice a day, L-DOPA: levodopa, PD: Parkinson’s disease.
6-OHDA: 6-hydroxydopamine, BID: twice a day, Ex-4: Exendin-4, MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, PD: Parkinson’s disease, LPS: lipopolysaccharide, GLP1R: glucagon-like peptide-1 receptor.
Ex-4: exenatide-4, mTOR: mechanistic target of rapamycin, IRS1: insulin receptor substrate 1, MDS-UPDRS: Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale, PD: Parkinson’s disease, PKB: protein kinase B, DAergic: dopaminergic, GLP1R: glucagon-like peptide-1 receptor.