Masitinib Shows Significant Prolonged Survival in ALS in Phase 3 Study


The effect observed in on ALSFRS-R at week 48 and progression-free survival further support the premise of greater treatment effect when masitinib is initiated earlier in the disease.

Jesus S. Mora, MD

Jesus S. Mora, MD

Orally administered masitinib (AB1010; AB Science), a tyrosine kinase inhibitor, showed the potential ability to prolong survival for up to 2 years in patients with mild or moderate amyotrophic lateral sclerosis (ALS) when used in combination with riluzole (Rilutek; Sanofi), according to newly published results from the phase 3 AB10015 clinical study (NCT02588677).1,2

Despite observing no long-term survival advantage for the overall masitinib 4.5 mg/kg/day cohort (LT-M4.5) of study AB10015 over placebo, investigators found an increasing improvement in median overall survival (OS) for masitinib in an enriched patient selected group. Statistical significance was reached for the LT-M4.5 cohort for those with at least 2 or greater on each baseline ALS Functional Rating Scale-revised (ALSFRS-R) item, with a median OS for masitinib (n = 50) of 69 months (95% CI, 44-non-estimate versus 44 months (95% CI, 31-62) for placebo (n = 63).

"This publication represents another significant scientific milestone in the search for a new treatment in ALS,” senior author Jesus S. Mora, MD, director, ALS Unit, Hospital San Rafael, said in a statement.1 “The magnitude of this observed survival signal for masitinib as compared with placebo is very encouraging and data from study AB10015 have now demonstrated a consistently significant treatment effect in terms of overall survival, hazard ratio, slowed rate of functional decline, and slowed deterioration in respiratory function and quality-of-life.”

The hazard ratio (HR) analysis was also significant for this cohort with a 44% reduced risk of death for masitinib-treated patients compared with those originally randomized to placebo (HR, 0.56 [95% CI, 0.33-0.97]; P = .037). These results were similar to the confirmatory AB19001 (NCT03127267) study population, with a significant median OS difference of 25 months in favor of masitinib (P = .037) and a significant 47% reduced risk of death (HR, 0.53 [95% CI, 31-92); P = .025).

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Named Patient Program (NPP) subpopulations, which compared patients that have remained in their assigned treatment arms following study AB10015 data readout, also indicated a consistent survival advantage in favor of masitinib. For example, the subpopulations of those who received masitinib 4.5 mg/kg/day (NPP-M4.5; n = 29) vs masitinib-naïve placebo (n = 53) showed a significant difference in median OS of 11 months (P = .008), corresponding to a significant 67% reduced risk of death in favor of masitinib (HR, 0.33 [95% CI, 0.12-0.88] P = .027). Masitinib-naïve placebo included 53 of 133 (40%) patients from the placebo arm that were alive in November 2017 but did not participate on the masitinib NPP.

Further cohorts of interest were patients pooled from both masitinib treatment arms (NPP-M4.5 plus NPP-M3.0, referred to as NPP-M[pooled]). Investigators also documented a significant difference in median OS (P = .008) with a between-group difference of 11 months and a 42% reduced risk of death (HR, 0.58 [95% CI, 0.28-1.19]; P = .134) in the analysis of NPP-M(pooled) (n = 59) versus masitinib-naïve placebo (n = 53).

Supportive analyses for masitinib patient enrichment showed between-group differences in improvements of both ∆ALSFRS-R and progression-free survival (PFS) with increasing degrees of enrichment. Considering the cohort most closely matched to the target population of study AB19001 (i.e., LT-M4.5 with ≥2 on each baseline ALSFRS-R item and disease onset to baseline [ΔFS] of <1.1 points/month), ∆ALSFRS-R for masitinib was –6.35 versus –11.03 for placebo, corresponding to a significant 42% slowing in rate of decline (P = .018), while PFS for this cohort showed a trend improvement of 13 months in favor of masitinib (P = .060).

"These long-term survival data, with an average follow-up of 75 months since diagnosis, suggest that masitinib can offer a substantial survival benefit when treatment is initiated before severe loss of functionality,” Albert Ludolph, MD, chairman, Department of Neurology, University Hospital and Facility of Ulm, said in a statement.1 “These findings are consistent with masitinib’s therapeutic objective for conservation of neuro-muscular functions. The current confirmatory phase 3 study (AB19001) in ALS patients with mild or moderate impairment of functionality at baseline, is very well-aligned with this population.”

The long-term survival results are consistent with masitinib’s mechanism of action, which significantly slows microglial-related disease progression, and prevents mast cell-related neuromuscular junctions denervation and Schwann call meditated neuroinflammation. Previously published results from the first phase 2b/3 study (AB10015) demonstrated that LT-M4.5 in combination with riluzole significantly slowed ALSFRS-R decline by 27% compared to riluzole alone at week 48 (P <.05).

1. Long-term follow-up of 75 months showed that masintib extended survival in amyotrophic lateral sclerosis by 25 months relative to placebo, provided that treatment starts early in disease course. News release. AB Science. July 19, 2021. Accessed July 19, 2021.
2. Mora JS, Bradley WG, Chaverri D, et al. Long-term survival analysis of masitinib in amyotrophic lateral sclerosis. Ther Adv Neurol Discord. Published June 19, 2021. doi: 10.1177/175628642110300365
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