A retrospective review of the progress in amyotrophic lateral sclerosis drug discovery over the last decade and a look at the latest strategies.

INTRODUCTION: Drug discovery for amyotrophic lateral sclerosis (ALS) has experienced a surge in clinical studies and remarkable preclinical milestones utilizing a variety of mutant superoxide dismutase 1 model systems. Of the drugs that were tested and showed positive preclinical effects, none demonstrated therapeutic benefits to ALS patients in clinical settings. AREAS COVERED: This review discusses the advances made in drug discovery for ALS and highlights why drug development is proving to be so difficult. It also discusses how a closer look at both preclinical and clinical studies could uncover the reasons why these preclinical successes have yet to result in the availability of an effective drug for clinical use. EXPERT OPINION: Valuable lessons from the numerous preclinical and clinical studies supply the biggest advantage in the monumental task of finding a cure for ALS. Obviously, a single design type for ALS clinical trials has not yielded success. The authors suggest a two-pronged approach that may prove essential to achieve clinical efficacy in the identification of novel targets and preclinical testing in multiple models to identify biomarkers that can function in diagnostic, predictive and prognostic roles, and changes to clinical trial design and patient recruitment criteria. The advancement of technology and invention of more powerful tools will further enhance the above. This will give rise to more sophisticated clinical trials with consideration of a range of criteria from: optimum dose, route of delivery, specific biomarkers, pharmacokinetics, pharmacodynamics and toxicology to biomarkers, timing for trial and patients' clinical status.