It has been said that late-stage clinical trials are where Alzheimer’s drugs go to die—there have been well over 130 failed clinical trials for Alzheimer’s in the last decade. Still, AB Science SA reported promising data from its Phase IIb/III trial of masitinib in patients with confirmed mild to moderate Alzheimer’s disease. And the approach is consistent with much of what is known about the disease’s pathology.
The study noted that there are currently four approved drugs for Alzheimer’s, donepezil, rivastigmine, galantamine and memantine. The study evaluated different doses of masitinib in patients with confirmed mild to moderate Alzheimer’s disease when administered as an add-on therapy to one or more of these drugs.
The trial demonstrated that 4.5 mg/kg/day of masitinib generated a significant treatment effect compared to the control arm on the primary endpoint of change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). It also showed that masitinib created a significant change from baseline in Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score.
Significantly fewer patients receiving masitinib hit the severe dementia stage compared to the placebo group after 24 weeks of treatment.
The safety was deemed acceptable and consistent with what was previously known about the drug. In it, 79.5% had at least one adverse event compared to 74.6% in the control arm; 5.9% had at least one serious adverse event (non-fatal) in the masitinib arm compared to 2.9% in the control arm, and 18.9% of patients had at least one severe adverse event in the masitinib arm compared to 16.8% in the control arm.
About two weeks ago, the French company also reported on a clinical trial of masitinib with gemcitabine in pancreatic cancer. The drug combination was associated with significant increases in survival in the confirmatory Phase III trial. The drug is being evaluated in neurology, inflammatory diseases and oncology. It is also being tested in amyotrophic lateral sclerosis (ALS). A recent study from the University of Chicago found that the drug, when compared with 1,900 other clinically safe drugs, was the strongest candidate for studies in COVID-19.
Masitinib is an oral, highly selective tyrosine kinase inhibitor.
“There is a vacuum of treatment options for patients with Alzheimer’s disease and today very few attempts to address the population with confirmed mild or moderate dementia associated with Alzheimer’s disease,” said Bruno Dubois, professor of Neurology at the Neurological Institute of the Salpetriere University Hospital at Paris and coordinating investigator of the AB09004 study. “These data are very encouraging and may provide new hope for patients with Alzheimer’s disease. The fact that masitinib could significantly reduce the proportion of patients reaching the stage of severe dementia is particularly interesting because this stage of the disease represents a significant burden for the society.”
For Alzheimer’s disease, the rationale for masitinib is associated with two possible mechanisms of action. The first is the role of mast cells in neuroinflammation and regulation of the blood-brain-barrier (BBB) permeability. The second is the inhibition of the protein kinase Fyn, which is involved in amyloid-beta signaling and tau phosphorylation. Both amyloid-beta and tau are proteins that abnormally accumulate in the brains of Alzheimer’s patients. Typically, amyloid-beta occurs earlier in the disease and tau appears later.
Neuroinflammation is becoming increasingly associated with Alzheimer’s disease. Mast cells release significant amounts of proinflammatory mediators and seem to play an important role in contributing to the inflammation in the central nervous system. They are also found on both sides of the BBB. Masitinib blocks mast cells by inhibiting the tyrosine kinases c-Kit and Lyn.
Alzheimer’s is also associated, as mentioned above, with amyloid-beta and tau. Fyn has been implicated in the pathogenesis of Alzheimer’s disease via its dual role in amyloid-beta signaling and tau phosphorylation. Masitinib inhibits Fyn, potentially disrupting the amyloid-beta signaling cascade and modulating the phosphorylation of tau.
“Results from study AB09004 are refreshing as they provide a radically new approach for the treatment of Alzheimer’s disease, and are extremely promising, in particular considering the robustness of the effect observed on cognitive function,” said Philip Scheltens, professor of Cognitive Neurology and director of the Alzheimer Center at the VU University Medical Center in Amsterdam. “I am eager to support AB Science’s endeavor to address such a devastating disease.”