The anti-inflammatory medication masitinib met its primary endpoint in an Alzheimer’s disease trial, according to topline data announced December 16 by its sponsor, the Paris-based company AB Science. In the six-month Phase 2b/3 study of 718 AD patients, the drug appeared to halt cognitive decline, with the treatment group, on average, notching slight improvements on the ADAS-Cog. In addition, fewer patients on drug than placebo progressed to severe dementia. The trial, which started seven years ago, did not include any biomarker data.

  • Masitinib maintained cognition and function in people with mild to moderate AD.
  • The drug is believed to dampen inflammation via microglia and mast cells.
  • An upcoming Phase 3 trial will include biomarker data.

In a December 17 webcast, company representatives said they will start a confirmatory Phase 3 AD trial next year. Masitinib is a veterinary medication used for animal cancer. It is also in trials for other neurodegenerative diseases, including amyotrophic lateral sclerosis and progressive multiple sclerosis.

“I find the results encouraging, particularly because nothing [else] seems to be working in mild to moderate AD,” Elena Galea at the Universitat Autònoma de Barcelona, Spain, wrote to Alzforum. In the webcast, Philip Scheltens at VU University, Amsterdam, praised the approach. “It’s encouraging to see new modes of action being pursued, and I’m happy to see a properly conducted Phase 2 trial,” Scheltens said. Other Alzheimer’s researchers struck a cautious note, saying they wanted to see more detailed data on how masitinib affects the brain.

Masitinib inhibits receptor tyrosine kinases, in particular c-kit on mast cells and CSF1R on macrophages and microglia. It is approved only for veterinary use to shrink mast cell tumors. However, many researchers have become interested in its broader potential to dampen inflammation. For example, in a mouse model of amyloidosis, chronic treatment with masitinib restored spatial learning and synaptic density in the hippocampus (Li et al., 2020). AB Science had previously tested masitinib in a small Phase 2a trial of 34 AD patients, where it stabilized cognition over six months (Piette et al., 2011). 

AB Science started the current study in 2013 in Spain, Romania, Poland, Ukraine, Bulgaria, and Greece. Participants had an average age of 72; about half had mild AD, defined as an MMSE of 21–25, and the remainder moderate, defined as an MMSE of 12–20. They could have a history of stable medication with cholinesterase inhibitors and/or memantine. The trial was designed to have three treatment arms: 3 mg/kg, 4.5 mg/kg, and a titration arm that took patients from 4.5 to 6 mg/kg. Recruitment was slow, however, leading the researchers to eventually abandon the 3 mg/kg arm to focus on the higher doses.

The 4.5 mg/kg arm ended up with 182 participants on drug and 176 on placebo. The placebo group declined slightly on the ADAS-Cog over 24 weeks, while the treatment group improved by 1.5 points. The difference was significant at p=0.0003. The trial used a functional measure, ADCS-ADL, as a co-primary endpoint. If either endpoint was below p=0.025, the trial was considered positive. On the ADCS-ADL, the placebo group declined and the treatment group improved, but the difference missed significance at p=0.038. The treatment group trended better on secondary measures, including the MMSE, CDR, and the neuropsychiatric inventory (NPI). Treated participants were less likely to progress to severe dementia, defined as an MMSE less than 10, with only 1 percent doing so, compared with 6 percent of controls.

In the titration arm, which had its own placebo control group, findings were not significant. Both the 186-person treatment group and, curiously, also the 91-person control group improved slightly on the ADAS-Cog and ADCS-ADL, with the treatment group numerically better on each. Possibly, this unexpected outcome in the placebo group obscured any drug benefit, AB Science CEO Alain Moussy suggested. Alternatively, 4.5 mg/kg may be enough to fully block the target receptors, with higher drug amounts leading to harmful off-target effects, he speculated. Supporting this idea, a similar pattern cropped up in a trial of masitinib for progressive MS, where 4.5 mg/kg benefitted patients, delaying disease progression by four months, while titration to 6 mg/kg did not.

The drug was generally well-tolerated, but there were more than twice as many serious adverse events in the treatment groups: 13 percent compared with 5 percent in control groups. These side effects followed no obvious pattern, being scattered among different organ systems. The safety issue deserves further study, Scheltens said.

Paul Aisen at the University of Southern California in San Diego noted some unusual features in the study design. For example, it is standard in mild to moderate AD trials to require both primary endpoints to meet the statistical threshold. “We need to wait for more study details, including the protocol and statistical analysis plan, to understand the significance of the reported results,” he wrote.

Others wanted more information on the drug’s mechanism of action. “A kinase inhibitor having an effect on AD is interesting and unique,” Jeroen Hoozemans at Amsterdam University Medical Center wrote to Alzforum. “It would be interesting to test masitinib in human microglial models to reveal the exact mechanism. This could also give insight into dose-dependent effects,” he added. Galea agreed, “Clarifying the mechanism of action is necessary for future comparisons with drugs targeted to microglia, astrocytes, or vascular cells.”

AB Science researchers believe that masitinib may act in several ways to aid AD brain. The drug has been shown to cross the blood-brain-barrier, implying it could act directly on microglia to dampen their destructive impulses. Microglia in AD brain gobble synapses and ramp up harmful inflammation. Inhibition of mast cells may also be critical to masitinib’s beneficial effects. In mouse models of amyloidosis, deleting mast cells has similar protective effects to masitinib treatment, the researchers found. These cells have received little attention in AD research. Finally, masitinib inhibits the protein kinase Fyn, which has been tied to amyloid and tau pathology, hinting that the drug could affect those processes (Jul 2010 conference news). 

In the upcoming Phase 3 trial, researchers will use biomarker data to examine the effects of treatment on different brain pathologies. They will test only the 4.5 mg/kg dose, and will include more participants at earlier stages of AD. The company will also continue to develop the drug for MS and ALS (May 2017 news). 

In other drug news, the RAGE receptor inhibitor azeliragon did not slow cognitive decline in a Phase 2 study of 43 people with mild AD and diabetes. The drug had previously failed efficacy in a Phase 3 AD trial, but a subgroup analysis suggested a possible benefit for people with diabetes (Apr 2018 news; Nov 2018 conference news). However, over six months, participants taking 5 mg azeliragon notched similar declines on the ADAS-Cog14 as did controls. The drug’s sponsor, vTv Therapeutics Inc, said in a press release that it will continue to analyze the data.—Madolyn Bowman Rogers


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Therapeutics Citations

  1. Masitinib
  2. Azeliragon

News Citations

  1. Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
  2. Certain Cancer Drugs Held Out as Prospects for ALS Therapy
  3. Fighting RAGE No Help to Alzheimer’s Disease Patients
  4. Trials of Diabetes-Related Therapies: Mainly a Bust

Paper Citations

  1. . Effects of Chronic Masitinib Treatment in APPswe/PSEN1dE9 Transgenic Mice Modeling Alzheimer's Disease. J Alzheimers Dis. 2020;76(4):1339-1345. PubMed.
  2. . Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther. 2011 Apr 19;3(2):16. PubMed.

External Citations

  1. announced
  2. Phase 2b/3
  3. Phase 2a
  4. Phase 2
  5. press release

Further Reading