KYOTO, Japan — Masitinib added to therapy with riluzole slowed the rate of progression of amyotrophic lateral sclerosis (ALS) in terms of deterioration measured on the ALS Functional Rating Scale-Revised (ALSFRS-R) and by measures of quality of life, respiratory function, and survival.
These effects were apparent for patients with an ALSFRS-R progression rate of less than 1.1 points per month, the researchers say.
“The sooner the treatment, the better the response,” Jesus S. Mora, MD, from Hospital San Rafael, Madrid, Spain, told delegates here at the XXIII World Congress of Neurology (WCN). In addition, milder symptoms predicted better response.
ALS confers a short life expectancy, and there is no cure. It is characterized by microgliosis and aberrant glial cells regulated by the CSF1/CSF1R signaling pathway.
Masitinib, an oral tyrosine kinase inhibitor, inhibits proliferation and migration in the central and peripheral nervous systems of microglia, macrophages, and mast cells expressing CSFR1 and c-Kit.
In the double-blind, placebo-controlled AB10015 study, patients aged 18 years or older who had a disease duration of up to 36 months, had a forced vital capacity (FVC) of 60% or greater, and were receiving stable dosing with riluzole were randomly assigned 1:1:1 to masitinib 4.5 mg/kg per day, masitinib 3.0 mg/kg per day, or placebo, all with riluzole, for 48 weeks.
The patients were categorized as “normal progressors,” those with a progression rate of less than 1.1 points per month on the ALSFRS-R, and “faster progressors,” who had a rate of 1.1 points or more per month. The primary efficacy population was the normal progressors in the masitinib 4.5mg/kg/day group, and the primary endpoint was the change in the ALSFRS-R score at 48 weeks.
For normal progressors taking masitinib 4.5 mg/kg/day plus riluzole, masitinib demonstrated significant benefit compared with placebo plus riluzole. Over the 48 weeks of the trial, the rate of decline in the ALSFRS-R was –0.77 points per month with masitinib compared with –1.05 points per month with placebo — a 27% slowing of ALSFRS-R over 48 weeks.
The median survival was 20 months (95% confidence interval [CI], 14 – 30 months) with masitinib 4.5 mg/kg per day vs 16 months (95% CI, 11 – 19 months) with placebo (P = .0159).
The patients receiving masitinib also had a 29% slowing of deterioration (P = .0078) as measured by the ALS Assessment Questionnaire-40, a patient self-report of health status involving the domains of physical mobility, activities of daily living and independence, eating and drinking, communication, and emotional reactions. The FVC showed a 22% slowing in the rate of deterioration with masitinib (P = .0296).
Table. Change in ALSFRS-R at 48 Weeks for the Primary Efficacy Populationa
| Treatment | Patients (n) | Least Squares Mean Difference From Baseline | Difference of Means (95% CI) | P Value |
|---|---|---|---|---|
| Masitinib 4.5 mg/kg per d + riluzole | 99 | –9.24 | 3.3878 (0.6451–6.1305) | .0157 |
| Placebo + riluzole | 102 | –12.63 | ||
| aAmong patients assessable for the primary endpoint. | ||||
Subgroup analyses of the primary efficacy population showed better results the earlier that masitinib was initiated and for patients with milder symptoms. For patients with a disease duration less than 18 months, there was a 32% slowing in deterioration of ALSFRS-R. For disease duration less than 24 months, there was a 25% slowing of ALSFRS-R decline.
Milder symptoms and shorter disease duration predicted slowing of progression: For a score of 2 or more points on each of the 12 items in the ALSFRS-R and less than 24 months of illness, there was a 45% decline in the rate of decline on the ALSFRS-R.
Dr Mora concluded that the safety of the combined treatment of masitinib 4.5 mg/kg per day and riluzole was acceptable. The frequency of adverse effects (AEs) in the placebo vs masitinib groups was 78.9% vs 88.4%, respectively; of serious non-fatal AEs, 18.0% vs 31.0%; and of severe AEs, 16.5% vs 29.5%. Common AEs with masitinib were rash, nausea, diarrhea, and weight loss. No deaths were considered related to treatment with either drug.
John England, MD, professor and chairman of the Department of Neurology at Louisiana State University School of Medicine, New Orleans, and editor-in-chief of the Journal of Neurological Sciences, told Medscape Medical News that he found the study “very interesting, and we desperately need more treatments for ALS. The standard treatment for over 20 years has been riluzole, but it really only slows the disease a very mild amount.”
He noted that a newly approved drug, edaravone, also may slow the disease, but probably only in select, younger, less affected patients. “So this drug [masitinib] is interesting because it’s showing, at least in the preliminary study, that it may have a mild degree of slowing of the disease.”
A major concern he had with the study is the high dropout rate in both the masitinib and placebo groups. Thus, one would need to calculate how that affected the power of the study. “When you have a dropout rate more than 20%, you have to reassess the study to make sure that the intention-to-treat analysis is valid and that the statistics bear up,” he said.
Dr England suggests further studies but finds the present one encouraging, “especially since it’s an oral medicine it would be easy to give [and] might be another addition” to the available treatments for ALS, in contrast to edaravone, which “is an intravenous medicine that has to be given very frequently.”
He said that the combination of masitinib and riluzole “seemed to have a pretty good safety profile.” Even if it has a mild effect on the disease, “it can certainly add something,” he said.
“Now that we have riluzole, we have edaravone, one would wonder if you could add another medicine and have a greater effect. The analogy would be in the treatment of cancer, where we for years have treated cancers with multiple medicines simultaneously, and I think that that may be one of the things that we’re going to need to do in a serious neurological disease like ALS…. We probably are going to need to use combinations of drugs to have a more robust effect on the disease.”
The US Food and Drug Administration has granted masitinib an orphan drug designation for ALS. However, in May, Bloomberg Markets reported that France’s National Safety Agency for Drug and Health Products ordered French biotech company AB Science, the developer of masitinib, to suspend clinical trials in France for an indication for treatment of mastocytosis “because of flaws in previous studies” and “to properly manage its database of side effects,” the agency said.
The company said at that time that it had corrected the deficiencies and hoped to restart trials after independent audits had been conducted and submitted.
However, AB Science said the order from the French regulatory agency should not affect trials for the ALS indication because those trials were taking place outside of France.
Dr England has disclosed no relevant financial relationships.
XXIII World Congress of Neurology (WCN). Abstract 529. Presented September 19, 2017.
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