Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial.
Alzheimer’s disease
Mast cells
Microglia
Tyrosine kinase inhibitor
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
28 02 2023
28 02 2023
Historique:
received:
01
08
2022
accepted:
15
01
2023
entrez:
28
2
2023
pubmed:
1
3
2023
medline:
3
3
2023
Statut:
epublish
Résumé
Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD). Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population. Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed. Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data. EudraCT: 2010-021218-50. gov : NCT01872598.
Sections du résumé
BACKGROUND
Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer's disease (AD).
METHODS
Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12-25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.
RESULTS
Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, -1.46 (95% CI [-2.46, -0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [-0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15 (97.5% CI [-3.48, -0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [-0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [-0.48, 2.50]) (representing an overall functional improvement) versus -0.81 (95% CI [-2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.
CONCLUSIONS
Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.
TRIAL REGISTRATION
EudraCT: 2010-021218-50.
CLINICALTRIALS
gov : NCT01872598.
Identifiants
pubmed: 36849969
doi: 10.1186/s13195-023-01169-x
pii: 10.1186/s13195-023-01169-x
pmc: PMC9972756
doi:
Substances chimiques
masitinib
M59NC4E26P
Memantine
W8O17SJF3T
Thiazoles
0
Banques de données
ClinicalTrials.gov
['NCT01872598']
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase III
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
39Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
Références
Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577–90.
pubmed: 33667416
pmcid: 8354300
doi: 10.1016/S0140-6736(20)32205-4
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10(9):698–712.
pubmed: 21852788
doi: 10.1038/nrd3505
Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37.
pubmed: 25024750
pmcid: 4095696
doi: 10.1186/alzrt269
Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–39.
pubmed: 31564456
pmcid: 6778042
doi: 10.1016/j.cell.2019.09.001
Sandhu JK, Kulka M. Decoding mast cell-microglia communication in neurodegenerative diseases. Int J Mol Sci. 2021;22(3):1093.
pubmed: 33499208
pmcid: 7865982
doi: 10.3390/ijms22031093
Klegeris A. Microglial targets for effective therapies of Alzheimer’s disease. Front Drug Chem Clin Res. 2020;3:1–4.
Tchessalova D, Posillico CK, Tronson NC. Neuroimmune activation drives multiple brain states. Front Syst Neurosci. 2018;12:39.
pubmed: 30210310
pmcid: 6123349
doi: 10.3389/fnsys.2018.00039
Li JW, Zong Y, Cao XP, Tan L, Tan L. Microglial priming in Alzheimer's disease. Ann Transl Med. 2018;6(10):176.
pubmed: 29951498
pmcid: 5994530
doi: 10.21037/atm.2018.04.22
Dubreuil P, Letard S, Ciufolini M, et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One. 2009;4:e7258.
pubmed: 19789626
pmcid: 2746281
doi: 10.1371/journal.pone.0007258
Vermersch P, Brieva-Ruiz L, Fox RJ, et al. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1148. Published 2022 Feb 21. https://doi.org/10.1212/NXI.0000000000001148 .
Mora JS, Genge A, Chio A, et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(1-2):5–14.
pubmed: 31280619
doi: 10.1080/21678421.2019.1632346
Trias E, King PH, Si Y, et al. Mast cells and neutrophils mediate peripheral motor pathway degeneration in ALS. JCI Insight. 2018;3(19):e123249.
pubmed: 30282815
pmcid: 6237484
doi: 10.1172/jci.insight.123249
Shahidehpour RK, Higdon RE, Crawford NG, et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging. 2021;99:19–27.
pubmed: 33422891
pmcid: 8293930
doi: 10.1016/j.neurobiolaging.2020.12.003
Kwon HS, Koh SH. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener. 2020;9(1):42.
pubmed: 33239064
pmcid: 7689983
doi: 10.1186/s40035-020-00221-2
Schwabe T, Srinivasan K, Rhinn H. Shifting paradigms: the central role of microglia in Alzheimer's disease. Neurobiol Dis. 2020;143:104962.
pubmed: 32535152
doi: 10.1016/j.nbd.2020.104962
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–72.
pubmed: 33318676
doi: 10.1038/s41582-020-00435-y
Kang YJ, Diep YN, Tran M, Cho H. Therapeutic targeting strategies for early- to late-staged Alzheimer's disease. Int J Mol Sci. 2020;21(24):9591.
pubmed: 33339351
pmcid: 7766709
doi: 10.3390/ijms21249591
Streit WJ, Khoshbouei H, Bechmann I. The role of microglia in sporadic Alzheimer's disease. J Alzheimers Dis. 2020. https://doi.org/10.3233/JAD-201248 .
Fani Maleki A, Rivest S. Innate immune cells: monocytes, monocyte-derived macrophages and microglia as therapeutic targets for Alzheimer's disease and multiple sclerosis. Front Cell Neurosci. 2019;13:355.
pubmed: 31427930
pmcid: 6690269
doi: 10.3389/fncel.2019.00355
Kempuraj D, Mentor S, Thangavel R, et al. Mast cells in stress, pain, blood-brain barrier, Neuroinflammation and Alzheimer's disease. Front Cell Neurosci. 2019;13:54.
pubmed: 30837843
pmcid: 6389675
doi: 10.3389/fncel.2019.00054
Jones MK, Nair A, Gupta M. Mast cells in neurodegenerative disease. Front Cell Neurosci. 2019;13:171 Published 2019 Apr 30.
pubmed: 31133804
pmcid: 6524694
doi: 10.3389/fncel.2019.00171
Nordengen K, Kirsebom BE, Henjum K, et al. Glial activation and inflammation along the Alzheimer's disease continuum. J Neuroinflammation. 2019;16(1):46.
pubmed: 30791945
pmcid: 6383268
doi: 10.1186/s12974-019-1399-2
Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. 2018;217(2):459–72.
pubmed: 29196460
pmcid: 5800817
doi: 10.1083/jcb.201709069
Skaper SD, Facci L, Zusso M, Giusti P. An inflammation-centric view of neurological disease: beyond the neuron. Front Cell Neurosci. 2018;12:72.
pubmed: 29618972
pmcid: 5871676
doi: 10.3389/fncel.2018.00072
Shaik-Dasthagirisaheb YB, Conti P. The role of mast cells in Alzheimer's disease. Adv. Clin Exp Med. 2016;25(4):781–7.
Folch J, Petrov D, Ettcheto M, et al. Masitinib for the treatment of mild to moderate Alzheimer's disease. Expert Rev Neurother. 2015;15(6):587–96.
pubmed: 25961655
doi: 10.1586/14737175.2015.1045419
Li T, Martin E, Abada YS, et al. Effects of chronic Masitinib treatment in APPswe/PSEN1dE9 transgenic mice modeling Alzheimer's disease. J Alzheimers Dis. 2020;76(4):1339–45.
pubmed: 32623401
doi: 10.3233/JAD-200466
Piette F, Belmin J, Vincent H, et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011;3(2):16.
pubmed: 21504563
pmcid: 3226277
doi: 10.1186/alzrt75
Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K. Alzheimer's disease drug development pipeline: 2020. Alzheimers Dement (N Y). 2020;6(1):e12050.
pubmed: 32695874
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry. 1984;141:1356–64.
pubmed: 6496779
doi: 10.1176/ajp.141.11.1356
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer’s disease: the Alzheimer’s disease cooperative study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S33–9.
pubmed: 9236950
doi: 10.1097/00002093-199700112-00005
Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer’s disease cooperative study—clinical global impression of change. Alzheimer Dis Assoc Disord. 1997;11(suppl 2):S22–32.
pubmed: 9236949
doi: 10.1097/00002093-199700112-00004
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.
pubmed: 1202204
doi: 10.1016/0022-3956(75)90026-6
Morris JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–4.
pubmed: 8232972
doi: 10.1212/WNL.43.11.2412-a
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, D.C.: American Psychiatric Association; 2000.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology. 1984;34:939–44.
pubmed: 6610841
doi: 10.1212/WNL.34.7.939
Taljaard M, Donner A, Klar N. Imputation strategies for missing continuous outcomes in cluster randomized trials. Biom J. 2008;50(3):329–45.
pubmed: 18537126
doi: 10.1002/bimj.200710423
Kenward M. Controlled multiple imputation methods for sensitivity analyses in longitudinal clinical trials with dropout and protocol deviation. Clin Invest. 2015;5:311–20. https://doi.org/10.4155/cli.14.132 .
doi: 10.4155/cli.14.132
Molinuevo JL, Frölich L, Grossberg GT, et al. Responder analysis of a randomized comparison of the 13.3 mg/24 h and 9.5 mg/24 h rivastigmine patch. Alzheimers Res Ther. 2015;7(1):9.
pubmed: 25755685
pmcid: 4353453
doi: 10.1186/s13195-014-0088-8
Jack CR Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87(5):539–47.
pubmed: 27371494
pmcid: 4970664
doi: 10.1212/WNL.0000000000002923
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614–29.
pubmed: 24849862
doi: 10.1016/S1474-4422(14)70090-0
Oremus M. Does the evidence say a 4-point change in ADAS-cog score is clinically significant? Alzheimers Dement. 2014;10(3):416–7.
pubmed: 24630567
doi: 10.1016/j.jalz.2013.12.017
Rockwood K, Fay S, Gorman M, Carver D, Graham JE. The clinical meaningfulness of ADAS-cog changes in Alzheimer's disease patients treated with donepezil in an open-label trial. BMC Neurol. 2007;7:26 Published 2007 Aug 30.
pubmed: 17760991
pmcid: 2034585
doi: 10.1186/1471-2377-7-26
Vellas B, Andrieu S, Sampaio C, Coley N, Wilcock G, European Task Force Group. Endpoints for trials in Alzheimer's disease: a European task force consensus. Lancet Neurol. 2008;7(5):436–50.
pubmed: 18420157
doi: 10.1016/S1474-4422(08)70087-5
Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2018;6(6):CD001190 Published 2018 Jun 18.
pubmed: 29923184
Birks JS, Chong LY, Grimley EJ. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2015;9(9):CD001191.
pubmed: 26393402
Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;2006(1):CD005593 Published 2006 Jan 25.
pubmed: 16437532
pmcid: 9006343