How are new medications created? How does an idea for a treatment lead to the development of a product? How do you choose the right target and optimal mechanisms of action?
The underlying hypothesis when it comes to creating a medicine, is that the active chemical entity in the drug has a specific biological target in the body which, once engaged, affects downstream processes. However, in the case of complex diseases with unknown underlying causes, where multiple pathways and mechanisms are involved, it may be ineffective to address a single target.
Therefore, when examining the current developments for ALS treatments, one can make out a shift in the paradigm. Although some companies are still working according to the conventional drug development routes, such as Alexion and AB Science, and others are focused on developing niche therapies for specific gene mutations that are thought to cause ALS, such as Biogen, several companies in the field have recognized the potential efficacy of drugs and treatments that target multiple pathologies of ALS, revolutionizing the industry. These treatments can be split into two main philosophies; stem cells and combination therapy.
Stem cell therapies are based on the use of cells which have not fully differentiated, and therefore have the potential to become many different cell types. Companies such as KadimaStem, Seneca Biopharma and CoreStem manipulate these cells in culture, and then inject them into the spinal cords of ALS patients, where they are expected to replace and/or support damaged cells of the central nervous system. These innovative therapies are being tested in patients, and although they can be considered invasive, with many possible safety issues, they may also have the potential to slow disease progression.
The second, safer approach is the use of combination therapies, which are being explored by Amylyx Pharmaceuticals and NeuroSense Therapeutics. Both companies are developing oral drugs consisting of a combination of two previously approved small molecules with known safety profiles. Each of the drugs separately work on specific pathological targets of ALS, and together demonstrate a synergistic effect.
Amylyx, a company that targets Endoplasmic Reticulum (ER) stress and mitochondrial dysfunction with their drug AMX0035, has recently announced positive results from their phase II clinical trial in patients with ALS, where they showed that in comparison to the placebo, the treatment slowed the disease by ~25% and extended survival by 6.5 months. The company is currently in the process of requesting approval for the drug in Canada and Europe.
NeuroSense (for full disclosure – authors of this article) is developing PrimeC, which targets RNA dysregulation, neuroinflammation and iron accumulation. Following remarkable preclinical studies, NeuroSense has recently concluded a successful proof-of-concept study in 15 patients with ALS in Israel, showing safety of PrimeC and positive clinical signals. NeuroSense is currently preparing for a pivotal, seamless phase II/III study to show efficacy of PrimeC in a large number of patients in order to gain approval by authorities.
Despite the failures of three pivotal clinical trials over this past year (Brainstorm Cell Therapeutics, Orphazyme and Orion Corporation), Amylyx’s success and NeuroSense’s promising results echo the recent change in the therapeutic approach, whereby no single agent can do the job for ALS and other neurodegenerative diseases. Therefore, a combined approach is the key for an effective treatment in these complex multifactorial indications. Through this change, the field has shifted gears and is closer than ever to approving multiple therapies for ALS.
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