Study finds common medications that could be repurposed to treat ALS
Researchers analyzed electronic medical records of more than 11,000 US veterans
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A study identified common medications that may extend survival in ALS patients.
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These include statins, PDE5 inhibitors, and alpha-adrenergic blockers.
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Combining statins and alpha-blockers showed greater survival benefits in veterans.
Several commonly used medications may be repurposed to extend survival in people with amyotrophic lateral sclerosis (ALS), according to an analysis of the electronic medical records of more than 11,000 U.S. veterans.
Researchers found that certain classes of medications were associated with improved survival in ALS, including statins, which are used to lower cholesterol; PDE5 inhibitors, which are common medications for high blood pressure and erectile dysfunction; and alpha-adrenergic blockers, which are used for high blood pressure and to ease symptoms of an enlarged prostate.
People taking both statins and alpha-adrenergic blockers appeared to have an even greater survival benefit, the team noted.
“What stood out was that there were multiple drugs in each of these groups that had the same positive effect,” Priyadip Ray, PhD, a research scientist at the Lawrence Livermore National Laboratory (LLNL) in California and study author, said in a press release. “This gave us a great deal of confidence in the relationship between slowing ALS progression and these drugs.”
The study, “Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study,” was published in The Lancet Digital Health.
ALS occurs more often in military veterans than the general population
ALS is caused by the progressive degeneration of specialized nerve cells in the brain and spinal cord that control muscle movement. It usually begins in adulthood and gradually leads to loss of muscle control.
Current treatments — such as riluzole (sold as the oral suspension Tiglutik and generic tablet formulations) and Radicava (edaravone) — have been shown to modestly slow disease progression and extend survival, but they do not stop the disease. A newer therapy, Qalsody (tofersen), targets changes in the SOD1 gene, but it is only applicable to a small number of ALS patients.
In the search for new treatments, one promising approach is drug repurposing — the practice of identifying new therapeutic uses for already approved drugs. Because these medications have been evaluated and their safety is well understood, they may reach patients more quickly than entirely new therapies.
With advances in artificial intelligence (AI), computational approaches such as machine learning, which use algorithms to learn from large datasets to uncover otherwise hidden patterns and connections, have been applied in drug repurposing studies.
However, due to the rarity of ALS, sufficiently large datasets to support such AI approaches for identifying new treatments have not been readily available — until now.
For reasons that are not fully understood, ALS occurs more often in military veterans than in the general population. As a result, the disease was formally recognized as a service-connected disease in 2009, leading to a sharp increase in veterans receiving ALS care. This generated an extensive treatment dataset spanning more than a decade within the Veterans Affairs (VA) healthcare system.
“We realized that the large amount of experience with treating ALS in the VA system could provide an alternative approach to identifying medications for the disease,” Ray said.
18 medications were associated with longer ALS survival
For their study, researchers analyzed the electronic health records (EHRs) of 11,003 individuals in the U.S. Veterans Health Administration database who were diagnosed with ALS between 2009 and 2019.
Instead of using traditional machine learning, the researchers employed a causal inference approach. This method aims to assess whether a treatment has a true effect by accounting for potential sources of bias, differences between patient groups, and uneven treatment patterns that often occur in real-world medical data.
“Our team developed a set of methods that combine rigorous statistical techniques with modern machine learning to isolate causal effects at the population level, even when data aren’t collected in a controlled way,” said co-author Braden Soper, PhD, an LLNL data scientist.
In their analysis, 27 of 162 medications assessed were linked to meaningful changes in the risk of death. Of these, 18 were associated with longer survival, while nine were linked to shorter survival.
The researchers found that several drugs within the same classes showed similar patterns associated with longer survival, including HMG-CoA reductase inhibitors, also called statins (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and alpha-adrenergic blockers (tamsulosin and terazosin).
To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS
To make sure the ALS diagnoses in the data were accurate, the team repeated the analysis solely in people who had been prescribed riluzole. In this group, several medications were associated with longer survival, including lovastatin, sildenafil, tamsulosin, and cholecalciferol (vitamin D).
Some medications linked to shorter survival were those commonly used to treat symptoms associated with advanced ALS, such as breathing difficulties, problems with speech or swallowing, cognitive changes, and depression. Drugs frequently used in end-of-life care (opiates and alprazolam) were also associated with reduced survival. Notably, riluzole was associated with shorter survival in this analysis.
Further analysis found that people taking both statins and alpha-adrenergic blockers showed an even greater survival benefit, suggesting that combining certain medications might have additive effects, the team noted.
Finally, a separate protein network analysis exploring how these medications might influence disease progression suggested that drugs associated with longer survival may affect shared biological pathways. For PDE5 inhibitors and statins, in particular, these pathways involve the metabolism of lipoproteins, which include HDL, known as “good cholesterol,” and LDL, known as “bad cholesterol.”
“To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS,” the researchers wrote. “We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.”
