UPDATE (May. 1, 2023)

  • Qalsody, Tofersen

Action: Antisense oligonucleotide (ASO) against superoxide dismutase 1 (SOD1) suppresses SOD1 expression.

The subjects are patients with familial ALS with SOD1 mutations*. 

Previous study results: No change was observed for the primary endpoint of ALSFRS-R (rate of symptom progression) in the double-blind period at six months (p=0.97).

Future extension studies hope to show the effect of the drug on slowing the rate of progression in the initial active drug group compared to that in the initial placebo group.


Clinical trial results: Phase III: There was no positive effect on the primary efficacy endpoint of change from baseline in ALSFRS-R total score at 28 weeks (double-blind period) in the primary analysis group (rapid progressive group) (placebo n=21; active n=39) (between-group difference 1.2; p=0.97). Serious neurologic adverse events (myelitis, meningitis, lumbar disc disease, intracranial hypertension, and papilledema) occurred in approximately 7% of patients with active drug. Zero occurred in the placebo group.(Miller et al., 2022)

However, a trend in favor of Tofelsen was observed for the secondary and exploratory endpoints (motor function, respiratory function, and quality of life) (Miller et al., 2021).

Tofelsen treatment significantly decreased the CSF neurofilament light chain (NLF) level, indicative of neuronal damage [60% reduction in active group and 20% increase in placebo group in the rapidly progressive group].

In an open-label extension study (after 12 months), ALSFR was 3.5 points (95% [CI]:0.4-6.7) and lung capacity (vital capacity) was 9.2% (95% CI:1.7-16.6) higher in the initial active drug group compared to that in the initial placebo group.

ClinicalTrials.gov Identifier: NCT03070119

Dosage: Monthly intrathecal injection

Side effects: In addition to adverse events related to lumbar puncture (headache, back pain, etc.), serious neurological events, including myelitis, occurred in the Tofelsen group.

Clinical Trials Status: On July 26, 2022, the FDA agreed to review a new drug application for tofersen. The application is based on a Phase 3 study that showed a greater reduction in neurofilament light chain NfL levels (a marker of transcellular damage) in the actual drug group. On 22 March 2002, the Advisory Committee stated that the reduction in neurofilaments was likely to indicate a clinical benefit for tofersen. However, the Committee voted that the data to date did not provide substantial evidence to support approval. However, the FDA granted accelerated approval (25 April 2023) on the basis that the reduction in neurofilaments was likely to provide a clinical benefit. For accelerated approval, efficacy must be demonstrated in subsequent studies.

A Phase III ATLAS clinical trial was initiated to test whether starting Tofelsen treatment in pre-onset individuals with SOD1 gene mutations can delay the onset of clinical symptoms.

ClinicalTrials.gov Identifier: NCT04856982 

Participants are being recruited.

Expected completion: August 2027

Remarks: Carriers with familial ALS who have a rapidly progressive SOD1 mutation, but are not yet symptomatic, are eligible.




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