Repurposed Cancer Drug Shows Promise in Alzheimer's

The addition of the antitumor medication masitinib to standard of care significantly slowed cognitive deterioration and improved overall functioning for patients with mild to moderate Alzheimer's disease (AD), results of a phase 3 study show.

Over 24 weeks, masitinib, added to standard of care, significantly slowed cognitive deterioration and improved overall functioning ― and therefore "could be an important new treatment option" for patients with mild to moderate AD, said lead investigator Bruno Dubois, MD, with Hôpital La Salpêtrière, Paris, France.

The study was presented at the Alzheimer's Association International Conference (AAIC) 2021.

Neuroprotective Properties

Masitinib, which is used to treat mast cells, also has demonstrated neuroprotective action in neurodegenerative diseases, Dubois told conference delegates.

"Interestingly, preclinical evidence showed that masitinib restores normal spacial learning performance and promotes recovery of synaptic markers in mouse model of AD. Clinical proof of concept that masitinib slows progression in mild to moderate AD was previously demonstrated in a small phase 2 trial," he noted.

The phase 2B/3 AB09004 study comprised two independent, double-blind, placebo-controlled, substudies: masitinib 4.5 mg/kg/d vs placebo, and titrated masitinib 6.0 mg/kg/d vs matched placebo.

The trial included a total of 719 patients who had received a clinical diagnosis of mild to moderate AD and who had been taking a stable dose of a cholinesterase inhibitor ― donepezil, rivastigmine, or galantamine ― and/or memantine for at least 6 months.

The two primary outcomes were change from baseline at 24 weeks in scores on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale.

At 24 weeks, compared to placebo, masitinib 4.5 mg/kg/d led to a statistically significant improvement in ADAS-Cog score. The mean difference from baseline was -1.46 with masitinib vs 0.69 with placebo (least-squares mean difference between groups: -2.15; 95% CI: -3.48 to -0.81; P < .001).

There was also a statistically significant improvement in ADCS-ADL score in the masitinib 4.5 mg/kg/d group at 24 weeks (change from baseline: 1.01 vs -0.81; least-squares mean difference between groups: 1.82; 95% CI: -0.15 to 3.79; P = .038).

The response rate (a secondary endpoint) was also significantly improved in the masitinib 4.5 mg/kg/d group compared with the placebo group (22.5% vs 13.1%; odds ratio: 1.96; 95% CI: 1.11 to 3.46; P = .020).

No treatment effect was seen with the 6.0 mg/kg/d dose. The safety of masitinib was "acceptable and was consistent with a known safety profile of the drug with no new safety signal."

This study is the "first successful" phase 3 study in mild to moderate AD of a drug targeting the innate immune cells of the neuroimmune system, Dubois told delegates.

He noted that a limitation of the trial was the lack of biomarker evidence to support modification of underlying disease processes or proof-of-target engagement. A confirmatory pivotal trial that includes biomarker outcomes is underway.

Narrow Therapeutic Window

Commenting on the results for Medscape Medical News, Howard Fillit, MD, neuroscientist and founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, noted that masitinib and some other tryrosine kinase inhibitors are being "repurposed from their cancer indications" for potential use in AD.

This study of masitinib is "interesting, with improvement seen on some of the critical endpoints, so it looks like there might be a signal here, but there's a need for another confirmatory trial and we'll see where it goes from here.

"The therapeutic window here might be narrow, because it was only the 4.5 mg/kg/d dose that was safe and effective," Fillit said.

He noted that the mechanism of action of masitinib in AD is "probably inhibition of inflammation by damping down the microglial reactivity in the brain.

"Ultimately, all of these drugs and different classes ― like the anti-amyloid monoclonals and the anti-inflammatory drugs and others ― will have to be combined, because each one alone doesn't look like they're going to have a huge effect," Fillit noted.

Funding for the study was provided by AB Science. Dubois has received grants/research support from Roche and Foundatino Merck-Avenir and honoraria or consultation fees from AB Science and Biogen. Fillit has disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2021: Session 4-HO-04. Presented July 29, 2021.

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