Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

ABSTRACT

Introduction: Amyotrophic lateral sclerosis (ALS), one in a family of age-related neurodegenerative disorders, is marked by predominantly cryptogenic causes, partially elucidated pathophysiology, and elusive treatments. The challenges of ALS are illustrated by two decades of negative drug trials.

Areas covered: In this article, we lay out the current understanding of disease genesis and physiology in relation to drug development in ALS, stressing important accomplishments and gaps in knowledge. We briefly consider clinical ALS, the ongoing search for biomarkers, and the latest in trial design, highlighting major recent and ongoing clinical trials; and we discuss, in a concluding section on future directions, the prion-protein hypothesis of neurodegeneration and what steps can be taken to end the drought that has characterized drug discovery in ALS.

Expert opinion: Age-related neurodegenerative disorders are fast becoming major public health problems for the world’s aging populations. Several agents offer promise in the near-term, but drug development is hampered by an interrelated cycle of obstacles surrounding etiological, physiological, and biomarkers discovery. It is time for the type of government-funded, public-supported offensive on neurodegenerative disease that has been effective in other fields.

KEYWORDS:

• Amyotrophic lateral sclerosis
• biomarkers treatment
• clinical trials
• glutamate neurotoxicity
• neurodegeneration
• neuroprotection
• pathophysiology

Article highlights

• Since the approval of riluzole in 1996, more than 30 successive phase III trials in ALS have yielded negative results.

• Elucidation of target mechanisms, identification of reliable biomarkers and greater attention to dose selection as well as interactions with riluzole should improve trial outcomes.

• Combined disease markers such as genetic mutations and metabolic signatures could aid stratification in trials, characterize clinical heterogeneity and facilitate the development of directed therapy.

• Transplantation of different types of stem cells, immune-based therapies and drugs targeting misfolded proteins are new approaches that are undergoing development.

• Personalized medicine, in which treatments target an individual patient’s disease based on etiologies and pathophysiological mechanisms, is a future goal

• Neurodegenerative diseases are outsized in their near-term financial and societal impact, but underfunded relative to comparable diseases. Dramatic increases in research funding are needed if the next 20 years are to see successes replace the disappointments of the past.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.