FDA Greenlights Phase 3 Trial of Masitinib for Alzheimer’s Disease

New study focuses on safety and efficacy in mild to moderate cases

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by Joana Vindeirinho, PhD |

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AB Science is initiating a Phase 3 trial to evaluate the safety and efficacy of its candidate therapy masitinib in patients with mild to moderate Alzheimer’s disease.

The company has received approval for this study from the U.S. Food and Drug Administration (FDA), as well as authorities in several European countries.

These approvals show that “masitinib is considered as a credible Alzheimer’s disease drug candidate,” Olivier Hermine, MD, PhD, president of the scientific committee of AB Science, said in a press release.

Several new therapy candidates target the early stages of Alzheimer’s. By contrast, masitinib will be evaluated in patients with mild to moderate disease.

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These patients make up “the most prevalent … population of patients with mild and moderate dementia,” Hermine said, adding that such a population has been “particularly challenging for clinical studies over the last twenty years and continues to have a very high unmet medical need.”

Masitinib is an oral medication that blocks the activity of innate immune cells present in the central nervous system (brain and spinal cord), such as mast cells, macrophages, and microglia. It does this by inhibiting the function of a protein called tyrosine kinase.

These cells regulate neuroinflammation, and evidence shows that they contribute to the progression of neurodegenerative disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and progressive forms of multiple sclerosis (MS).

Masitinib is currently approved for veterinary use. However, its inhibitory action on innate immune cells has made it a promising therapy candidate for several human diseases. In recent years, masitinib was shown to have potential therapeutic use in progressive multiple sclerosis, as well as ALS.

Clinical trials results

The potential of masitinib as a disease-modifying therapy was also shown for Alzheimer’s in a Phase 2b/3 trial called AB09004 (NCT01872598). The trial was sponsored by AB Science.

In the study, 182 patients with mild to moderate Alzheimer’s received masitinib (4.5 mg/kg per day) as an add-on to standard treatment with cholinesterase inhibitors and/or Namenda (memantine). In the control group, 176 patients received standard therapy and a placebo.

The trial also tested an increasing dose regimen of masitinib, which was raised from 4.5 mg/kg per day to 6 mg/kg per day after three months.

The trial’s primary goal was to assess changes after 24 weeks of treatment in two scores: ADAS-Cog, which tracks changes in cognition and memory, and ADCS-ADL, which evaluates self-care and activities of daily living.

When given at a dose of 4.5 mg/kg per day, masitinib significantly improved cognition after 24 weeks of treatment compared with placebo, with a change of -1.46 (representing improvement) in the ADAS-Cog score. By contrast, cognition continued to decline in the placebo group, with a change of +0.69 (representing decline).

Patients who received masitinib also had an improvement in the measure of self-care and activities of daily living. However, this change was not considered statistically significant when compared with the placebo group.

In terms of safety, 87% of patients receiving masitinib at a dose of 4.5 mg/kg per day had at least one side effect, or adverse event. In the placebo group, this proportion was 77.5%.

Similarly, more patients in the masitinib group experienced a severe adverse event (26.5%) than in the placebo group (19.3%).

Phase 3 trial plans

The upcoming Phase 3 trial, called AB21004 (NCT05564169), aims to confirm these findings. It is also sponsored by AB Science.

AB21004 will assess the safety and efficacy of masitinib as an add-on to cholinesterase inhibitors and/or Namenda, versus a placebo. Masitinib dosing will start at 3 mg/kg per day before being increased to 4.5 mg/kg per day after four weeks, subject to a safety control.

The trial is estimated to enroll 600 patients ages 50 and older with a confirmed clinical diagnosis of mild and moderate Alzheimer’s disease. Participants are also required to have received a stable dose of cholinesterase inhibitors and/or Namenda for at least six months before the trial start.

The primary goal of AB21004 is to assess changes after 24 weeks of treatment with masitinib in the two measures of cognition and function used in the AB09004 trial.

Secondary goals include assessing changes in cognition and function, as well as time to severe dementia, after a longer period of 48 weeks.

Recruitment has not yet started for AB21004. Although trial sites have not been announced, they are expected to be in Europe and the U.S.

“We are very happy to be initiating this international phase III study of masitinib in the United States, especially since there are very limited treatment options for patients with mild or moderate Alzheimer’s disease,” said Jeffrey Cummings, MD, director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas.