DUBLIN – Could a tyrosine kinase inhibitor approved for treating canine cancer offer clinical benefits in Alzheimer’s disease? That’s the bold claim AB Science SA is making, after unveiling top-line data from a phase IIb/III trial in which it reported that a subgroup of patients on a twice daily 4.5-mg/kg dose of oral masitinib experienced “a significant treatment effect” as compared with placebo after 24 weeks. The company’s stock (Paris:AB) gained as much as 69% on the news before closing Dec. 16 at €14.34 (US$17.46), up 39% on its previous close.
The study recruited 721 patients with mild to moderate Alzheimer’s disease. Their Mini-Mental State Examination (MMSE) scores ranged from 12 to 25 on the 30-point scale, in which a score below 12 equates to severe dementia. The study had two primary endpoints, based on changes in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), which measures cognitive function, and changes in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCSADL) score. All patients were also allowed to take a cholinesterase inhibitor and/or memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist.
The apparent effect seems to be most pronounced on ADAS-Cog, which measures cognitive function. Although the Paris-based company has yet to disclose the magnitude of the effect, it reported that the change from baseline among those in the active treatment group (n=182) vs. the change from baseline among those in the placebo group (n=176) was highly statistically significant (p=0.0003).
It also reported a statistically significant difference (p=0.0381) between the active treatment and control arms in terms of change in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCSADL) score, from baseline to 24 weeks. Moreover, it has reported that mean ADAS-Cog, ADCS-ADL and MMSE scores of those in the active treatment group actually improved over both 12 and 24 weeks, whereas they all worsened among those in the control group, although it did not report the magnitude of those effects. The dropout rate was 5.9% for those on drug vs. 2.9% for those on placebo. “The safety is acceptable for this fragile population,” AB Science CEO Alain Moussy told BioWorld.
Further data will be presented during a webcast with key opinion leaders Dec. 17. For external observers, the one big question is why the effects seen in the 4.5-mg/kg dose group were not repeated in a group who received a twice-daily 4.5-mg/kg dose for three months, followed by a twice-daily 6-mg/kg dose for the second three months of the trial. “We don’t see statistical significance on this dose,” Moussy said. That may be because the 6-mg/kg dose of masitinib does not offer any additional efficacy, he said, but the higher dose may be driving excessive platelet-derived growth factor (PDGF) inhibition – a recognized activity of masitinib – given the importance of PDGF in maintaining certain cellular phenotypes in the central nervous system.
Moussy attributed the reported effects in the 4.5-mg/kg group to the inhibitory effect of masitinib on mast cell and on microglial activity, through targeting the c-Kit receptor. That leads both to protective effects on neuronal synapses and to anti-inflammatory effects, without impacting the beta-amyloid cascade. “We don’t reduce aggregate formation, but we stop the vicious cycle,” Moussy said. Supporting evidence comes from preclinical studies on transgenic mice. A subsidiary effect may also occur through inhibition of the Fyn kinase, which interacts with both tau and the beta-amyloid signal pathways.
But the main effects seen in Alzheimer’s mirror effects seen in amyotrophic lateral sclerosis (ALS) and progressive multiple sclerosis, where the drug is undergoing phase III and phase II studies, respectively. “We think it’s likely that mast cells play a critical role in neurological disease, in MS, in ALS and in Alzheimer’s disease,” he said.
Confirmatory study up next
In Alzheimer’s, the path to registration for the product is now clear, Moussy said. “The next step is to launch a confirmatory study in key countries.” The company aims to get that underway in the U.S. and Europe as quickly as possible. “By 2023, we should have data,” he said.
If it’s successful, it would represent a remarkable turnaround for the company and for the molecule. AB Science has, for more than a decade, tested masitinib in a broad range of indications, including various cancers, neurodegenerative conditions, asthma, and orphan diseases such as mastocytosis. A phase II study in COVID-19 is currently recruiting, after an independent drug repurposing screen suggested it may have potential in that indication.
Its history is clouded, however, by an EMA rejection in 2017 of an application for the drug in mastocytosis, following an inspection that uncovered “serious failings” in the conduct of the study and changes made during the course of the study that made the results difficult to interpret. AB Science has since restructured its clinical development team and has resumed development of the drug, which has been available as a veterinary drug for more than a decade. It would be an extraordinary twist if this became a significant option for Alzheimer’s patients, too.