Rethinking ALS Treatment: Beyond a One-Size-Fits-All Approach

Clinical trials for amyotrophic lateral sclerosis (ALS) often yield disappointing outcomes, and the recent failure of Amylyx's Relyvrio in its Phase III trial was no exception. Despite the drug's Phase II results indicating a 33% slower progression rate and a significant survival benefit, the FDA had granted approval based on these promising signs, along with the drug's safety and the company's commitment to withdraw it if further studies proved it ineffective. Now, the drug's future remains uncertain.

This marks the third consecutive failure of an ALS drug in Phase III trials within a year, with the second being an FDA-approved drug. Mitsubishi Tanabe halted a Phase IIIb trial for edaravone (Radicava), citing its lack of superior efficacy over existing treatments. Ferrer's different formulation of oral edaravone also failed in Phase III. The efficacy of edaravone has always been questionable, with mixed results from its original trials and a lack of real-world evidence supporting its benefits.

The situation underscores the fact that nearly three decades after the approval of riluzole, which at best extends life by a few months, it remains the only ALS drug with proven efficacy. As someone deeply involved in ALS research and overseeing numerous translational research projects, the current state of drug development is a cause for serious concern. The optimistic approach to ALS drug development must be reevaluated, as the one-size-fits-all strategy has not yielded satisfactory results.

ALS, like other neurodegenerative diseases, is highly variable in its onset and progression patterns. While some cases are hereditary, the majority occur without a clear genetic cause, suggesting that ALS may not be a single disease but rather a spectrum of overlapping conditions. This heterogeneity is a significant factor in the development of ALS drugs, as it implies that a universal cure may not exist.

The analogy to cancer treatment is apt, as the success in increasing five-year survival rates to over 70% from 50% in 1975 is largely attributed to tailored treatments based on cancer subtypes. In contrast, ALS research and drug development often overlook this heterogeneity, relying on models that may not be representative of the majority of patients and including trial participants without considering their biological suitability for the drug.

The protein TDP43, implicated in 97% of ALS cases, plays a crucial role in the disease's pathology. When TDP43 malfunctions, it leads to the production of rogue proteins, which contribute to cell death. However, the composition of these proteins can vary significantly between patients, influenced by genetics and epigenetics. This variability suggests that while there may be commonalities in ALS, such as the role of TDP43, there are also important differences that must be considered in drug development.

Recent findings have identified distinct gene expression patterns in non-hereditary ALS, indicating different subtypes of the disease. This discovery underscores the need for a more nuanced approach to drug development, one that takes into account the molecular diversity of ALS.

To move forward, it is essential to develop better models for non-hereditary ALS, utilize RNA sequencing and proteomics to understand disease subtypes, and create more accurate diagnostics to guide clinical trials. Investments in these areas, such as Takeda's $580 million investment in AcuraStem, signal a promising direction for ALS research. The FDA's approval of Qalsody for a specific genetic form of ALS also highlights the value of precision medicine.

The future of ALS drug development must embrace the complexity and heterogeneity of the disease. Only by doing so can we hope to avoid further disappointments like those experienced with Relyvrio and edaravone.