Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-023-01169-x |
| _version_ | 1797841155345350656 |
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| author | Bruno Dubois Jesús López-Arrieta Stanley Lipschitz Triantafyllos Doskas Luiza Spiru Svitlana Moroz Olena Venger Patrick Vermersch Alain Moussy Colin D. Mansfield Olivier Hermine Magda Tsolaki for the AB09004 Study Group Investigators |
| author_facet | Bruno Dubois Jesús López-Arrieta Stanley Lipschitz Triantafyllos Doskas Luiza Spiru Svitlana Moroz Olena Venger Patrick Vermersch Alain Moussy Colin D. Mansfield Olivier Hermine Magda Tsolaki for the AB09004 Study Group Investigators |
| author_sort | Bruno Dubois |
| collection | DOAJ |
| description | Abstract 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 |
| first_indexed | 2024-04-09T16:26:29Z |
| format | Article |
| id | doaj.art-83c798131c8243d0a378ebbc75a7c528 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-04-09T16:26:29Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-83c798131c8243d0a378ebbc75a7c5282023-04-23T11:11:10ZengBMCAlzheimer’s Research & Therapy1758-91932023-02-0115111010.1186/s13195-023-01169-xMasitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trialBruno Dubois0Jesús López-Arrieta1Stanley Lipschitz2Triantafyllos Doskas3Luiza Spiru4Svitlana Moroz5Olena Venger6Patrick Vermersch7Alain Moussy8Colin D. Mansfield9Olivier Hermine10Magda Tsolaki11for the AB09004 Study Group InvestigatorsAlzheimer Research Center IM2A, Salpêtrière Hospital, AP-HP, Sorbonne UniversityCantoblanco Memory Clinic, Geriatric Department, Hospital CantoblancoThe Dr Stanley Lipschitz Clinic IncNeurological Department, Athens Naval HospitalCarol Davila University of Medicine and Pharmacy, The Excellence Clinic of Geriatrics, Gerontology and Old Age PsychiatryPsychosomatic Center Based on Psychoneurology Department of Communal Enterprise ‘Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov’, Dnipropetrovsk Regional CouncilDepartment Psychiatry, Narcology and Medical Psychology I. Horbachevsky Ternopil National Medical UniversityUniv. Lille, UMR Inserm U1172, CHU Lille, FHU PreciseAB ScienceAB ScienceAB ScienceFirst Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of ThessalonikiAbstract 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 : NCT01872598https://doi.org/10.1186/s13195-023-01169-xAlzheimer’s diseaseMast cellsMicrogliaTyrosine kinase inhibitor |
| spellingShingle | Bruno Dubois Jesús López-Arrieta Stanley Lipschitz Triantafyllos Doskas Luiza Spiru Svitlana Moroz Olena Venger Patrick Vermersch Alain Moussy Colin D. Mansfield Olivier Hermine Magda Tsolaki for the AB09004 Study Group Investigators Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial Alzheimer’s Research & Therapy Alzheimer’s disease Mast cells Microglia Tyrosine kinase inhibitor |
| title | Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial |
| title_full | Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial |
| title_fullStr | Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial |
| title_full_unstemmed | Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial |
| title_short | Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial |
| title_sort | masitinib for mild to moderate alzheimer s disease results from a randomized placebo controlled phase 3 clinical trial |
| topic | Alzheimer’s disease Mast cells Microglia Tyrosine kinase inhibitor |
| url | https://doi.org/10.1186/s13195-023-01169-x |
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