Real-world study sheds new light on safety of approved ALS drug

A post-marketing analysis of safety reports found that many of the strongest signals involving Qalsody (tofersen) in people with amyotrophic lateral sclerosis (ALS) were related to the spinal procedures used to administer it. Other reporting signals involved neurological and inflammatory events.

The study, based on 409 reports submitted to an FDA safety database, also detected possible new signals involving respiratory disorders, including seven reports of pulmonary embolism, a serious blockage of an artery in the lungs. The researchers said these findings require further study and highlight the importance of long-term safety monitoring.

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“This study is the first to systematically conduct a post-marketing [safety] analysis of [Qalsody]. It not only validated the common [adverse events] recorded in the drug labeling but also identified novel risk signals with potential clinical significance,” the researchers wrote.

The study, “Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database,” was published in Frontiers in Neurology.

ALS is a progressive neurological disease that damages motor neurons, the nerve cells responsible for controlling muscle movement. As these neurons gradually deteriorate and die, muscle weakness and disability worsen over time. Although the exact cause remains unclear, genetic and nongenetic factors, including environmental and lifestyle influences, are believed to contribute to ALS.

Mutations in the SOD1 gene are present in up to 20% of familial ALS and in up to 2% of sporadic ALS cases. Such mutations can lead to abnormal forms of the SOD1 protein that may accumulate, form toxic clumps, and damage nerve cells.

Qalsody is designed to reduce SOD1 levels by targeting SOD1 messenger RNA (mRNA), an intermediate molecule that carries the instructions for making the protein, for breakdown. By reducing SOD1 production, the therapy may slow disease progression and extend survival. It is administered directly into the spinal canal, or intrathecally, every 28 days after three loading doses given two weeks apart.

The treatment was granted accelerated approval in the U.S. based on a reduction in neurofilament light chain, a biomarker of nerve degeneration, that is reasonably likely to predict clinical benefit, with continued approval depending on confirmation of its clinical benefit.

FDA reports reveal key safety signals

Here, researchers in China, where the treatment received breakthrough approval in 2024, analyzed data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), a database that collects voluntary reports of side effects and other safety problems involving approved medicines.

A total of 409 reports naming Qalsody as the primary suspect drug were identified. Men accounted for more reports than women (47.4% vs. 43%). People ages 18 to 64 accounted for 43% of reports, compared with 16.6% for those ages 65 to 85 and 0.2% for those older than 85. Age information was unavailable for 40.1% of reports. Most reports came from the U.S. (72.9%).

Consumers submitted the largest share of reports (47.4%), followed by physicians (29.3%), other health professionals (11.7%), and pharmacists (4.6%). Among 110 reports with available timing data, the median time to onset of adverse events was 97.5 days, or about three months. Of those reports, 28.2% described events occurring within the first month and 21.8% described events occurring more than one year after treatment began. According to the researchers, this indicates “the need for attention to long-term drug safety.”

The reports included adverse events across 22 medical categories. The categories represented most often involved the nervous system (51.1%); injury, poisoning, and procedural complications (42.5%); general and administration-site conditions (31.5%); and musculoskeletal and connective tissue disorders (27.6%). Because one report could include events in more than one category, the percentages overlap.

More detailed analysis found that many of the strongest reporting signals involved spinal tap–related events and abnormalities in cerebrospinal fluid (CSF), consistent with Qalsody’s intrathecal administration. The most prominent signals included a reporting category called neurological procedural complications, red blood cells in CSF, increased white blood cell counts in CSF, and increased overall CSF cell counts. CSF is the fluid that surrounds the brain and spinal cord.

Known risks and possible new concerns emerge

The database also flagged rare but serious side effects already documented in Qalsody’s prescribing information. These include increased intracranial pressure (elevated pressure around the brain), papilledema, myelitis and radiculitis, and aseptic meningitis, or inflammation of the protective membranes surrounding the brain and spinal cord.

Researchers also identified signals in two broad medical categories not currently listed on the product label. Events involving the airways, lungs, and surrounding tissues appeared in 63 reports (15.4%), while events involving hearing and balance appeared in 10 reports (2.4%). According to the researchers, “their potential causal relationships need to be further verified through large-scale clinical studies.”

The study also detected a new reporting signal for pulmonary embolism based on seven reports. Pulmonary embolism is a blockage of an artery in the lungs, usually caused by a blood clot, and is not listed on the current label. The researchers emphasized that this “newly identified signal of pulmonary embolism suggests a potential thromboembolic risk in specific patient populations” that warrants close clinical monitoring and further investigation. They noted, however, that the relationship between Qalsody and blood-clotting events remains uncertain and requires further study.

“These findings provide real-world evidence to inform the balance between the therapeutic potential and safety profile of [Qalsody],” they added. “Future clinical strategies should focus on mitigating central nervous system-related and procedure-related adverse events.”