Masitinib in combination with Rilutek (riluzole) slows functional decline of patients with amyotrophic lateral sclerosis (ALS) who have a typical disease progression, according to the final report of AB Science‘s Phase 2/3 clinical trial.
At 11 months of treatment with the combo, the rate of disability progression was reduced by 27%, as compared to a placebo plus Rilutek. In contrast, patients who have a faster disease worsening do not benefit as much from adding masitinib to their treatment.
AB Science is now setting up a Phase 3 trial to confirm the latest results and gather more data in support of a new marketing application to the European Medicine Agency (EMA). The agency issued a negative opinion in April 2018, based on low reliability and robustness of the data, and possible bias in the primary analysis.
Full results of the trial are detailed in the report “Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial,” published recently in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.
“These results represent the most positive impact of a study in ALS since the riluzole studies, and I am happy to have contributed to this trial. … Moreover, study AB10015 represents the first positive phase 3 trial of a tyrosine kinase inhibitor in ALS, with publication of this article being a cornerstone in the development program of masitinib.” Mamede de Carvalho, M.D. said in a press release. De Carvalho is a neurologist at the University Hospital Lisboa-Norte, Portugal, and collaborator in the trial.
Study AB10015 was a Phase 2/3, double-blind, randomized trial (NCT02588677) comparing the safety and effectiveness of masitinib combined with the approved ALS medication Rilutek, against a placebo plus Rilutek.
The trial had broad inclusion criteria. Patients with disease duration up to 36 months or with a forced vital capacity (FVC) of at least 60% (a measure of lung function) could be enrolled.
There was no restriction on the revised functional rating score ALSFRS-R at study start, meaning that patients who already had lost certain physical abilities or who had a severely affected physical function (scores of 0 or 1 at inclusion on any of the scale’s components) could be included.
The study included 394 ALS patients who were randomized to receive either 4.5 or 3.0 mg per kg per day of masitinib combined with 100 mg per day of Rilutek, or a placebo and Rilutek, for up to 48 weeks (11 months).
The primary efficacy goal was changed from baseline to week 48 in ALSFRS-R, restricted to patients receiving the higher dose of masitinib and who had a “normal progression” of the disease (defined as an ALSFRS-R decline rate of less than 1.1 points per month) from disease-onset to baseline. This represents a typical ALS progression, happening in about 85% of the patients.
The study reached its primary goal and showed that treatment with this combination significantly slowed ALSFRS-R decline by 27% as compared with the Rilutek control group, at 48 weeks.
Sensitivity analyses, including the EMA’s recommended methods, all were significant and confirmed the main efficacy results.
Within the group of “normal progressors,” masitinib also led to a clinically meaningful 25% delay in progression-free survival (PFS) (defined here as the time until the earliest event between death and functional decline of at least 9 points in ALSFRS-R). This is an important endpoint (goal) recognized by the EMA to support registration in ALS.
Median PFS of masitinib-treated patients was 20 months, compared to 16 months for those receiving Rilutek and placebo.
The combo also delayed by 29% decline in quality-of-life, measured by ALSAQ-40 survey, and by 22% deterioration in lung function (FVC). compared to the placebo group.
Conversely, no significant benefit was detected if the analysis included patients whose disease progressed faster than normal, irrespective of masitinib doses. Overall survival of the full population of patients also was no different between masitinib or placebo groups.
A group analysis, however, suggests that if masitinib is initiated at a less severe stage of disease (scores higher than zero in ALSFRS-R items) then it significantly delays progression among “normal and fast progressors.”
“This represents a realistic clinical scenario in which treatment is initiated prior to severe symptom onset,” researchers stressed.
Masitinib safety was “acceptable” and consistent with its known risk profile, AB Science said. Rates of treatment-emergent side effects were 88%, 85% and 79% with masitinib dose 4.5, dose 3.0 and placebo, respectively. No deaths were related to masitinib.
“Indeed, this drug had a significant positive impact in a typical population of ALS patients, with a parallel impact on functional and respiratory decay, which supports an unquestionable positive effect on disease progression,” Carvalho said.
“These promising results generate hope in the scientific community to have a new treatment in this fatal disease. A confirmatory study will follow with participation of the key reference centers worldwide that should confirm this very encouraging data” said Philippe Corcia, MD, from the University Hospital Center of Tours, France.
Recently, the EMA validated a study design optimized by AB Science for its forthcoming Phase 3 trial.