A Tyrosine Kinase Inhibitor Produces Improvement in Early Stage Alzheimer's Patients
Senolytic drugs are those that selectively force senescent cells into programmed cell death. Senescent cells accumulate with age throughout the body, and their pro-inflammatory signaling is disruptive to tissue structure and function when maintained over the long term. Clearance of senescent cells has produced sizable, rapid reversal of age-related disease and improvement in health in mice. There are numerous classes of senolytic small molecule drugs, each class attacking the biochemistry of senescent cells from a different direction in order to force programmed cell death. The well-studied senolytic drug dasatinib is a tyrosine kinase inhibitor, and there is evidence for another tyrosine kinase inhibitor, nintedanib, to also be senolytic.
Today's open access paper concerns ongoing clinical trials of masinitib, another tyrosine kinase inhibitor, as a treatment for Alzheimer's disease. Cellular senescence in brain cells, particularly the supporting cells of the brain such as astrocytes and microglia, is implicated in the progression of Alzheimer's disease. The use of tyrosine kinase inhibitors in this context predates a growing understanding of their relevance to cellular senescence in aging, and so the paper here focuses reducing inflammatory activation of brain cells rather than putting this in terms of cellular senescence. It is unclear as to whether masinitib is in fact senolytic, but it would not be that surprising to find that it is. It is also worth noting that the dasatinib and quercetin senolytic combination is presently in early trials to treat Alzheimer's disease.
Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial
Masitinib is an oral tyrosine kinase inhibitor that has demonstrated neuroprotective action in neurodegenerative diseases via inhibition of mast cell and microglia/macrophage activity, and which is capable of accumulating within the central nervous system (CNS) at a therapeutically relevant concentration. There is a growing body of evidence implicating mast cells and microglia (types of innate immune cells that are present in the central nervous system), with the pathophysiology of Alzheimer's disease (AD). Masitinib has been shown to restore normal spatial learning performance and promote recovery of synaptic markers in a mouse model of AD, with its synapto-protective action being directly linked to mast cell inhibition. Previously, a small phase 2 trial showed that masitinib slows progression in mild-to-moderate AD patients. Here, we report findings from the first large randomized trial targeting activated neuroimmune cells for treatment of mild-to-moderate AD.
Masitinib was administered as an adjunct therapy to standard of care in 182 patients with mild to moderate dementia due to probable AD. After 24 weeks of treatment, masitinib (4.5 mg/kg/day) significantly slowed cognitive deterioration (as measured by the primary endpoint of ADAS-cog), with acceptable safety. Masitinib (4.5 mg/kg/day) showed significant benefit over placebo according to the primary endpoint of ADAS-cog, -1.46 (representing an overall improvement in cognition) versus 0.69 (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15. For the ADCS-ADL primary endpoint, the between-group difference was 1.82, i.e. 1.01 (representing an overall functional improvement) versus -0.81 (representing increased functional deterioration), respectively. Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia).
Multiple approved drug treatments and dosages for AD have demonstrated a similar change in ADAS-Cog (approximately 2-point) to that reported for masitinib (4.5 mg/kg/day) and this value is also consistent with published recommendations. The observed improvement in ADAS-Cog for masitinib (4.5 mg/kg/day) relative to control is therefore clinically meaningful. Conversely, results from the masitinib 6.0 mg/kg/day parallel group did not demonstrate any treatment effect. One explanation of this divergent result is that the 6.0 mg/kg/day parallel group placebo arm showed an atypical improvement over 24 weeks, as exemplified by the positive change from baseline in ADCS-ADL score