The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult‐onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small‐molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.

Duality of P2X7 Receptor in Amyotrophic Lateral Sclerosis

“…None of these are fully satisfactory, riluzole having modest benefits on survival of patients and edaravone halting ALS progression only during the early stages (Jaiswal, 2019). To date, more than 50 drugs have failed in ALS clinical trials, while several compounds are currently in interventional phase-III trials (Andrews et al, 2019;Wobst et al, 2020).…”

TRICALS: creating a highway toward a cure

“…A benefit to life expectancy remains, however, to be determined and riluzole remains the only available treatment for European patients with amyotrophic lateral sclerosis (ALS). Over 70 compounds have been tested (3), but despite considerable efforts from industry and academia, and promising early signals, none of the treatments has been effective in slowing the course of the illness or prolonging survival. The reasons for this failure in translation from animal models to human trials are multifactorial, but can be grouped into five major categories-namely: (1) disease heterogeneity and our relatively limited knowledge of the interplay between different disease mechanisms in humans;…”

Is There a Role for Vitamin D in Amyotrophic Lateral Sclerosis? A Systematic Review and Meta-Analysis

“…ALS is a neurodegenerative disease characterized by the progressive loss of motor neurons that leads to paralysis and respiratory failure 3–5 years after the onset of symptoms ( 2 ). Only two drugs are approved for ALS treatment, with only moderate efficacy on delaying disease progression or increasing survival, despite the large number of new and old drugs evaluated in clinical trials ( 3 , 4 ). These successive failures could be related to the fact that ALS is diagnosed 1 year after the onset of symptoms, a critical period for initiation of treatments that could prevent motor neuron degeneration.…”