Masitinib for ALS
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What is masitinib for ALS?
Masitinib, formerly known as AB1010, is an oral medication that’s being developed as a potential add-on treatment for slowing disease progression in amyotrophic lateral sclerosis (ALS).
The therapy is being tested in an ALS Phase 3 clinical trial, and also is under review for potential conditional approvals in the European Union and in Canada, where a decision is expected in November. The therapy will be marketed as Alsitek in both countries if an approval is ultimately granted.
AB Science, the company developing masitinib, also is exploring it as a potential treatment for a number of other conditions, including multiple sclerosis, Alzheimer’s disease, and several cancers.
Therapy Snapshot
| Treatment Name: | Masitinib |
| Administration: | Being tested in ALS in an oral tablet formulation |
| Clinical testing: | Now in Phase 3 clinical trials in ALS |
How does masitinib work in ALS?
Masitinib belongs to a class of medications called tyrosine kinase inhibitors. As the name implies, it works by blocking the activity of tyrosine kinases, a group of proteins important for a number of cellular processes, including cell maturation, growth, and death.
The medication specifically blocks tyrosine kinases that are essential for the function of certain immune cells, including macrophages, microglia, and mast cells. These are key cells of the innate immune system — a part of the immune system that serves as a first line of defense against infections — that are thought to drive inflammation and neurodegeneration in ALS.
It’s not known exactly what causes ALS, but numerous studies have suggested that uncontrolled inflammation may play a role. By blocking the activation of these immune cells, masitinib may help to reduce inflammation and slow ALS disease progression.
How will masitinib be administered in ALS?
Masitinib is available in the form of film-coated tablets that, in ALS clinical trials, were administered orally. The medicine has been tested at doses ranging from 3-6 mg/kg per day, but an ongoing Phase 3 trial is now investigating it at daily doses of 4.5 and 6 mg/kg.
In all ALS trials to date, masitinib has been administered as an add-on to the approved ALS treatment Rilutek (riluzole).
Masitinib in ALS clinical trials
In preclinical studies, masitinib significantly reduced inflammation, eased neurodegeneration, and extended survival in a mouse model of ALS. This led AB Science to begin testing the therapy in clinical trials involving ALS patients.
Phase 2/3 AB10015 trial
An initial Phase 2/3 clinical trial, called AB10015 (NCT02588677), enrolled 394 people with ALS whose symptoms had begun in the previous three years. All had normal disease progression, as measured by changes in the ALS Functional Rating Scale-Revised, known as ALSFRS-R. These normal progressors had an ALSFRS-R decline rate of less than 1.1 points per month from disease onset to the study’s start.
The participants were randomly assigned to receive either a placebo or masitinib, as add-on to Rilutek, for 48 weeks, or nearly one year. The daily dose of masitinib was 3 or 4.5 mg/kg.
The study’s main goal was to determine if treatment could slow disease progression, as assessed by ALSFRS-R, in patients who received the higher dose.
The results showed that the rate of decline on ALSFRS-R was significantly slower, by about 27%, in normally progressing patients receiving the higher dose of masitinib compared with those given a placebo. That higher dose also significantly slowed declines in lung function and quality of life.
No significant benefit was detected if the analysis included patients whose disease progressed faster than normal, irrespective of masitinib doses. However, the treatment significantly delayed disease progression in the whole group, including both normal and fast progressors, if initiated at a less severe stage.
Consistently, a long-term survival analysis showed no significant effect of masitinib in the overall group: median overall survival time was 46 months with masitinib compared with 40 months with a placebo.
However, patients with milder ALS — defined as a score of two or higher on every item of the ALSFRS-R upon entering the trial — showed significant survival benefits with masitinib. The median overall survival time was 69 months with masitinib, compared with 44 months with the placebo. That difference, of more than two years, represented a 44% reduction in the risk of death.
Trial data also suggested that patients given masitinib continued to experience a slower decline over time in functional status and lung function, and had better quality of life scores.
Ongoing Phase 3 trial
AB Science now is sponsoring a Phase 3 clinical trial (NCT03127267), called AB19001, that will include an estimated 495 adults with ALS. The eligibility criteria called for these participants to be less than two years out from a disease diagnosis.
The study is being conducted at dozens of sites across the U.S., in certain countries in Europe, and in Israel. It involves people with familial or sporadic disease who have a score of two or higher on every item of the ALSFRS-R scale and are on stable treatment with Rilutek.
Participants in the Phase 3 trial are being randomly assigned to take one of two daily doses of masitinib (4.5 or 6 mg/kg), or a placebo, for 48 weeks. For the first four weeks, those assigned to masitinib will receive the treatment twice daily, at a 3 mg/kg daily dose, after which they will escalate to the 4.5 mg/kg dose. Individuals in the higher dose group will then further increase their dose to 6 mg/kg a day after four weeks on the intermediate dosage.
The trial’s main goal is to assess the effect of treatment on disease progression, as measured by changes in ALSFRS-R scores. Other measures will evaluate the therapy’s impact on quality of life, lung function, muscle strength, and survival.
Common side effects of masitinib
In ALS clinical trials, the most commonly reported side effects of masitinib include:
- rash
- tissue swelling (edema)
- respiratory failure
- nausea
- diarrhea
- anxiety.
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FAQs about masitinib
Masitinib is an experimental oral therapy being investigated in clinical trials as a potential treatment for amyotrophic lateral sclerosis (ALS). The medication is designed to reduce the activity of immune cells thought to be involved in ALS progression by blocking specific proteins called tyrosine kinases. In clinical trials, the therapy helped to slow functional decline and significantly extended survival among patients.
AB Science, the company developing masitinib, is sponsoring a Phase 3 clinical trial to explore the efficacy of masitinib as an add-on therapy for amyotrophic lateral sclerosis (ALS). At present, it is too early to determine if or when the therapy might be up for approval by the U.S. Food and Drug Administration. The therapy now is being considered for conditional approval in Europe and in Canada.
The most common side effects reported in amyotrophic lateral sclerosis clinical trials of masitinib included rash, tissue swelling, respiratory failure, nausea, diarrhea, and anxiety. Yet, because the drug is still in clinical testing, its full safety profile may not be fully known. Patients taking masitinib should discuss the potential side effects of the medication with their healthcare provider.
The interaction between masitinib and alcohol has not been studied in-depth. It’s recommended patients talk to their healthcare team about whether and how much is safe for them to drink while taking any medication.
In a Phase 2/3 clinical trial in people with amyotrophic lateral sclerosis (ALS), a significant difference in disease progression rates was evident between masitinib and a placebo after about a year of treatment. However, patients given the therapy still experienced disease progression — just more slowly than what was seen with the placebo.
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