Tofersen, known by the brand name Qalsody, is a targeted therapy for a specific genetic form of amyotrophic lateral sclerosis (ALS). It is designed for adults whose disease is caused by a mutation in the superoxide dismutase 1 (SOD1) gene, which accounts for about 2% of all ALS cases. The treatment is not a cure for ALS but represents a focused approach to managing this uniformly fatal neurodegenerative condition by addressing a specific underlying genetic cause.
Tofersen’s Mechanism of Action
Amyotrophic lateral sclerosis linked to SOD1 gene mutations arises from the production of a toxic SOD1 protein. The mutated gene provides faulty instructions, leading to a misfolded protein that accumulates within motor neurons. This toxic buildup causes the nerve cells to degenerate, resulting in progressive muscle weakness. The SOD1 gene mutation is responsible for approximately 10-20% of familial ALS cases and 1-2% of sporadic instances of the disease.
Tofersen is an antisense oligonucleotide (ASO), a therapy that interferes with the production of specific proteins. This synthetic genetic material is designed to bind to the messenger RNA (mRNA) from the SOD1 gene. This binding triggers the degradation of the SOD1 mRNA, reducing the cell’s ability to create the toxic SOD1 protein and aiming to slow motor neuron damage.
Clinical Trial Outcomes on Disease Progression
The Phase 3 VALOR trial for Tofersen enrolled 108 adults with SOD1-ALS, who were randomly assigned to receive either the drug or a placebo for 28 weeks. The trial’s main goal was to measure change using the ALS Functional Rating Scale-Revised (ALSFRS-R), which assesses daily functions. During the initial 28-week period, the trial did not meet this goal, as the difference in functional decline between the groups was not statistically significant.
Encouraging signs emerged from the trial’s open-label extension (OLE), where all participants received Tofersen. In a comparison between those who started the drug immediately (early-start) and those who switched from placebo after 28 weeks (delayed-start), the early-start group showed a slower functional decline. After one year, the difference in ALSFRS-R scores between the groups was 3.5 points, suggesting that earlier treatment slows disease progression.
The longer-term data showed that the benefits of Tofersen on clinical function, respiratory capacity, and muscle strength become more apparent over time. While the initial phase lacked a clear functional benefit, the extended study provided evidence that Tofersen could alter the disease’s course. This supported its approval based on biomarker evidence, pending confirmation of further clinical benefit.
Effects on Biological Markers of Disease
Clinical trials also measured biological markers to assess Tofersen’s direct effect. Biomarkers are measurable substances that can indicate the presence or severity of a disease. For SOD1-ALS, two important markers are the SOD1 protein and neurofilament light chain (NfL), a protein fragment released into the blood and cerebrospinal fluid (CSF) when nerve cells are damaged.
The VALOR trial showed that Tofersen caused a substantial and sustained reduction of SOD1 protein in the CSF. At 28 weeks, the Tofersen group had a significant reduction compared to the placebo group. This finding confirmed the drug was working as designed by lowering the target protein.
Treatment with Tofersen also resulted in a significant decrease in NfL levels in both plasma and CSF, reducing them by about 50% in the bloodstream by 12 to 16 weeks. Since elevated NfL indicates ongoing neurodegeneration, this reduction suggested the treatment was lessening motor neuron damage. This biological evidence showed the drug’s impact on the disease process before functional benefits were apparent.
Safety Profile and Administration
Tofersen is administered into the cerebrospinal fluid via an intrathecal injection, also known as a lumbar puncture. The treatment begins with three loading doses given 14 days apart, followed by a maintenance dose every 28 days.
Common side effects were generally mild to moderate, and the injection procedure itself carries risks like headache and back pain. The most frequent side effects observed in trials include:
- Pain (such as in the back or limbs)
- Fatigue
- Joint pain (arthralgia)
- Muscle pain (myalgia)
- An increase in white blood cell count in the CSF
Less common but more serious neurologic events have also been reported, including:
- Myelitis (inflammation of the spinal cord)
- Radiculitis (inflammation of the nerve roots)
- Papilledema (swelling of the optic nerve)
- Aseptic meningitis (inflammation of the brain’s linings)
In clinical studies, some patients who developed myelitis or radiculitis discontinued treatment, while others were able to resolve symptoms without stopping the medication.