Masitinib reduces time to disability progression for patients with PPMS, non-active SPMS
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Treatment with masitinib, a first-in-class tyrosine kinase inhibitor, led to significant improvement in Expanded Disability Scale Status, or EDSS, for patients with MS, according to findings presented at MSVirtual2020.
“We know, in MS, that both adaptive immunity and innate immunity play a role. Many data suggest that microglia and mast cells are associated with the pathophysiology of MS, so it is a great opportunity to target the cells in patients with progressive MS,” Patrick Vermersch, MD, of CHU de Lille in France, said during his presentation. “Masitinib is an oral tyrosine kinase inhibitor that selectively targets mast cells and microglia activity and clinically demonstrated neuroprotective action in preclinical models of ALS and Alzheimer’s disease.”
Vermersch and colleagues evaluated the efficacy of oral masitinib for primary progressive MS (PPMS) and non-active secondary progressive MS (nSPMS) in a randomized, double-blind, placebo-controlled, 2-parallel group trial. Eligibility criteria included age (18-75 years), baseline EDSS (2-6) regardless of time from disease onset, and diagnosis (PPMS or nSPMS). assessed two independent parallel groups: 4.5 mg/kgday vs. matched placebo and a titrated masitinib dose of 6 mg/kgday vs. placebo.
Patients for 96 weeks. Overall EDSS change from baseline served as the primary endpoint. The researchers reported results as least-squares means difference (EDSS, with positive value indicating worsening) and treatment effect as between-group difference (LSM with negative value favoring masitinib).
The study met its primary outcome in demonstrating a statistically significant decrease in disability progression according to EDSS, Vermersch said during his presentation. Masitinib 4.5 mg/kg daily (n = 199; median EDSS = 5.5; mean age = 49.3 ± 9.6 years) resulted in a significant benefit compared with placebo (n = 101), with EDSS of 0.001 vs. 0.098, respectively, and LSM of 0.097 (95% CI, 0.192 to 0.002). This treatment-effect was numerically retained for the nSPMS (masitinib, n = 120; placebo, n = 56) and PPMS (masitinib, n = 79; placebo, n = 45), with an LSM of 0.104 (95% CI, 0.198 to 0.008) and 0.128 (95% CI, 0.285 to 0.0282), respectively.
All EDSS sensitivity analyses were convergent with the primary outcome, including the conservative jump-to-reference approach with LSM of 0.089 (95% CI, 0.173 to 0.006), according to Vermersch and colleagues. Ordinal EDSS analysis demonstrated a significant 39% relative probability of either decrease in EDSS progression or increase in EDSS improvement (HR = 0.61; 95% CI, 0.376-0.988). Analysis of EDSS time to progression revealed a significantly decreased relative risk of 42% with masitinib for first progression (HR = 0.58; 95% CI, 0.35-0.96) and a decreased relative risk of 37% with masitinib for 12-week confirmed (HR = 0.63; 95% CI, 0.33-1.2).
Nearly all patients (94.5%) experienced at least one adverse event with masitinib 4.5 mg/kgday compared with placebo (87.1%). The researchers observed safety signals consistent with the known profile for masitinib; common treatment-emergent adverse events included diarrhea, nausea, rash and hematological assessments.
Efficacy results from the masitinib high-dose parallel group, which received titrated 6 mg/kgday, were inconclusive and no new safety signal was noted.
The adverse events observed “were reversible and manageable,” Vermersch said. He also noted that, because the change in in EDSS with masitinib 6 mg/kgday was comparable to masitinib 4.5 mg/kgday, only the 4.5 mg dose would be evaluated further in MS.
“Masitinib is a first-in-class tyrosine kinase inhibitor targeting the innate immune system via inhibition of mast cells and microglia/macrophage activity,” Vermersch said. “The 37% reduction in risk of confirmed disability progression is relevant from a medical standpoint, the benefit was demonstrated across a broad population and the masitinib safety profile is suitable for long-term administration in this population. The agent may provide a new treatment option for PPMS and non-active SPMS.”
Perspective
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This trial is of interest for a number of reasons. One is that the drug, masitinib, has a novel mechanism of action. It is a tyrosine kinase inhibitor that we think has an impact on the innate immune system, which we is one of the driving mechanisms for progressive MS.
Second, the trial had some innovative design features. It combined secondary and primary progressive MS in a single trial and the way disability changes were measured was somewhat different than the way we’ve typically done it in other trials. The trial is also of interest because it did show efficacy for disability outcomes with the drug. Treatments for MS are a major unmet need in the field, so these are very hopeful results.
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Vermersch P, et al. Abstract FC04.01. Presented at: MSVirtual2020; Sept. 11-13, 2020 (virtual meeting).
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