Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001. Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity. Results: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31–0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001. Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.Fil: Mora, Jesus S.. No especifíca;Fil: Bradley, Walter G.. University of Miami; Estados UnidosFil: Chaverri, Delia. No especifíca;Fil: Hernández Barral, María. No especifíca;Fil: Mascias, Javier. No especifíca;Fil: Gamez, Josep. Universitat Autònoma de Barcelona; EspañaFil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Moussy, Alain. No especifíca;Fil: Mansfield, Colin D.. No especifíca;Fil: Hermine, Olivier. No especifíca;Fil: Ludolph, Albert C.. Universitat Ulm; Alemani

Oxidative stress in neurology and in neurodegenerative processes

Aging is one of the principal risk factors that play an important role in several human conditions and pathogenesis, primarily neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). A progressive loss of neurons, reduced motor or behavioral functions, and abnormally aggregated proteins define these conditions. An unbalanced redox environment, including the generation of excessive reactive oxygen species (ROS) or system deficiency, causes oxidative stress (OS). The brain is one of the principal organs that are particularly susceptible to ROS because of its elevated oxygen demand and the presence of abundant peroxidation-sensitivelipid cells. Previous studies have reported that widespread neurodegenerative disease pathophysiology involves OS. Cellular antioxidants are known to alter such redox status, target destruction, and regulate oxidative mechanisms engaged in cell proliferation, gene expression, signal transduction, and cell death pathway. Oxidants and antioxidants are important in maintaining free balance, metabolized, environmental-related radicals and the body’s antioxidant mechanisms. In biological systems, several complex natural antioxidant mechanisms occur that work together to prevent prooxidant damage. The objective of this chapter is to demonstrate that free radicals are engaged in neurodegenerative disease pathophysiology and that antioxidants and scavenging products help in the prevention and cure of such disease conditions. This chapter also examines the role of antioxidants in neurodegenerative illnesses, in their chemoprevention and therapy