Trials and Tribulations of ALS Drug Development

Amyotrophic lateral sclerosis (ALS) is a complex disease with multiple interacting pathologies, that presents itself differently in each patient, with varying rates of progression and sites of onset, making it especially challenging to develop an effective treatment. Furthermore, ALS is classified as an orphan disease – there are only an estimated half a million patients with ALS worldwide at any given moment. To be blunt, it just isn’t economical to develop a drug for such a small market.

However, regulatory authorities have come up with an interesting way to tackle the orphan disease issue. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) aim to incentivize companies to develop treatments for orphan diseases by granting orphan drug designations (ODD) to those targeting life threatening diseases with low prevalence. Companies who are granted ODDs are permitted seven or ten years of market exclusivity in the US and Europe, respectively, irrelevant of granted patents. Additionally, companies who have been granted ODDs can benefit from the offered financial impetus.

By definition, there are only small numbers of patients with orphan diseases, limiting the sample size for clinical trials, thereby cutting the costs of clinical development. This acts as further drive for companies to develop orphan treatments. However, due to the relatively low quantity demanded, companies price their rare disease treatments accordingly. 

For ALS specifically, it is unequivocal that there is low prevalence of the disease globally, therefore it is likely for orphan designations to be granted for companies developing drugs in the field, assuming there is scientific rationale and promising results. However, this does not consider the pressing problem of the complexity of the disease and its pathologies.

The notion that drug development for ALS is riddled with difficulties, is echoed by the fact that to this day, only two drugs have been FDA-approved for ALS, only one of which has been approved by the EMA as well. Riluzole, the standard of care for ALS today, was developed by Sanofi and was approved in the US in 1995, and in Europe in 1996. In clinical trials, Riluzole showed increased survival of 2-3 months. Then, following 20 years of failed clinical trials for other experimental pharmaceuticals, the FDA approved Mitsubishi-Tanabe’s Edaravone in 2017. Clinically, Edaravone showed a 30% slow in the decline of a subpopulation of patients with early-stage fast-progressing ALS. Both these drugs have unclear mechanisms of action, although it is known that Riluzole stimulates glutamate uptake.

In tandem with the mildly successful developments of Riluzole and Edaravone, a vast number of drugs have been tested in preclinical models of ALS. The scientific consensus utilizes the mouse model; this model uses different genetic mutations stimulating similar phenotypes as the disease in humans. Drugs which showed huge promise in these models, such as celecoxib, minocycline, creatine and thalidomide, failed to show efficacy in clinical trials in ALS patients. This may be due to preclinical models not being indicative and predictive enough in ALS. Furthermore, many experts argue that using a single compound to tackle a multifaceted disease is ineffective.

It is clear that new approaches need to be taken in the battle against ALS, and the accepted theory in the field today is that ALS must be tackled on multiple fronts, as no single bullet will suffice for such a complex disease. Recent developments by NeuroSense Therapeutics and few other cutting-edge companies have given rise to hope in the field, and the industry is beginning to see the merits in developing drugs for such a debilitating disease. This decade will bring us closer than ever to finding an effective treatment for ALS patients.

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* Writer's Credit: Avital Pushett ; Dr. Shiran Zimri ; Rebecca Solit ; Anastasia Joukovski ; Joel Grabinar