Masitinib works best in moderate ALS, new trial analysis shows

Combined with Rilutek, treatment slowed disease progression, improved lung function

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by Steve Bryson, PhD |

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Masitinib as an oral add-on therapy to Rilutek (riluzole) showed the greatest benefits in amyotrophic lateral sclerosis (ALS) patients with mild or moderate disease severity, an analysis of trial data showed.

The findings come from the now-complete AB10015 Phase 2/3 clinical trial (NCT02588677) that excluded people with very severe ALS. Because masitinib is designed to slow disease progression, patients with severe disease were unlikely to benefit from it, AB Science, the therapy’s developer, said in a press release.

While the the entire study population showed no survival benefit with masitinib versus a placebo, those with moderate ALS lived significantly longer with masitinib as an add-on treatment. The combined treatment also significantly slowed disease progression and improved lung function and quality of life in those patients without a complete loss of physical function in any activity at the study’s start.

Details of this new analysis, “Masitinib Shows Prolonged Survival in Amyotrophic Lateral Sclerosis (ALS) Patients with Mild or Moderate Disease Severity at Baseline,” were presented at the American Academy of Neurology (AAN) 2023 annual meeting last month.

Masitinib works by blocking the activity of specific tyrosine kinase enzymes that regulate the function of immune cells that cause inflammation. Its intended effect is to slow disease progression and alleviate symptoms.

The therapy was evaluated as an add-on treatment to the approved ALS therapy Rilutek in the 48-week AB10015 study and 394 patients were enrolled and assigned to one of two masitinib doses (3 or 4.5 mg/kg) or a placebo given daily for 48 weeks (about 11 months).

Final data showed a daily 4.5 mg/kg dose of masitinib plus Rilutek significantly slowed disease progression by 27% compared with Rilutek and a placebo. These outcomes occurred in patients with “normal” disease progression, defined as a decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores of less than 1.1 points a month.

The combination therapy also led to significantly slower declines in quality of life and lung function in patients progressing normally, but no changes were observed in those progressing faster than normal.

A group analysis suggested initiating masitinib at a less severe stage could result in significant reductions in disease progression in both normal and fast-progressing patients, however.

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Masitinib with Rilutek slowed disease progression

The new analysis focused on normally progressing participants with moderate ALS at the start (baseline) — defined as an ALSFRS-R score on every item of at least two points or higher.

In this subgroup, masitinib plus Rilutek significantly slowed progression by 42% versus Rilutek alone. Likewise, moderate patients had a median survival of 69 months with masitinib versus 44 months for placebo-treated patients — a 25-month improvement, representing a 44% reduction in mortality risk.

By comparison, across all trial participants, the median overall survival was 40 months for those given a placebo alone and 46 months with masitinib, a nonsignificant difference.

Researchers also examined the data on ALS patients who hadn’t yet had a complete loss of physical function, or a zero score on any of the 12 ALSFRS-R components. This analysis included those with normal and fast disease progression, and accounted for about 80% of AB10015 participants.

Using the combined assessment of function and survival (CAFS), a joint measure of survival and disease progression, there was a significant, 18.4% relative benefit in favor of daily 4.5 mg/kg of masitinib than Rilutek alone.

Consistently, ALSFRS-R scores declined 25% less by week 48 in patients receiving masitinib plus Rilutek compared with those given Rilutek alone. A 20.4% reduction was also seen in lung function decline with the combined therapy as well as a 19.8% decline in quality of life measures.

“Masitinib is most effective in patients with ‘moderate ALS’ and prior to any complete loss of function,” the researchers wrote.

To confirm these findings, AB Science is running the AB19001 Phase 3 clinical trial (NCT03127267), which expects to enroll up to 495 adults with mild to moderate ALS, diagnosed within the last two years. Participants will be randomly assigned a daily dose of masitinib (4.5 or 6 mg/kg) or a placebo, combined with Rilutek, for 48 weeks.

The trial’s primary outcome is if masitinib slows disease progression based on ALSFRS-R scores. Secondary measures include changes in lung function, muscle strength, quality of life, CAFS scores, and time to disease progression or death. Top-line results are expected this year.

Masitinib is currently under review for conditional approval in Europe and Canada. A recommendation from Europe’s Committee for Medicinal Products for Human Use (CHMP) is expected in the coming months and the Canadian review has been paused after the agency requested more information, which has already been filed by AB Science.