Tofersen VALOR Trial — SOD1-ALS Antisense Oligonucleotide (NEJM 2022)
Tofersen is the first antisense oligonucleotide approved for ALS and the first targeted therapy for a genetic form of the disease. The VALOR Phase 3 trial, published in the New England Journal of Medicine in 2022, enrolled 108 adults with SOD1-ALS — a subgroup accounting for about 2% of all ALS cases — and failed to meet its primary functional endpoint at 28 weeks. But biomarker data told a compelling story: tofersen dramatically reduced CSF SOD1 protein and plasma neurofilament light chain (NfL). The FDA granted accelerated approval in 2023 on the basis of NfL reduction as a surrogate biomarker. Long-term open-label extension data published in JAMA Neurology in December 2025 showed that approximately 25% of participants experienced functional stabilization or improvement at three years — an outcome unprecedented in ALS.
Mechanism of action: silencing mutant SOD1
Antisense oligonucleotides (ASOs) are short synthetic strands of nucleic acid that bind to a specific target messenger RNA, preventing it from being translated into the corresponding protein. Tofersen is designed to bind the mRNA encoding superoxide dismutase-1 (SOD1) — the first gene identified as causing familial ALS, in 1993.
In SOD1-ALS, a mutation in the SOD1 gene causes the SOD1 protein to misfold and aggregate, forming toxic species that damage motor neurons through mechanisms including mitochondrial dysfunction, oxidative stress, and ER stress. By reducing the amount of SOD1 protein produced — both mutant and normal, since the ASO targets all SOD1 mRNA — tofersen reduces the source of the toxic protein at a fundamental level.
Tofersen is administered as an intrathecal injection — directly into the cerebrospinal fluid via lumbar puncture — allowing it to reach motor neurons in the spinal cord at concentrations that cannot be achieved with systemic delivery across the blood-brain barrier.
VALOR Phase 3 trial design
VALOR enrolled 108 adults with genetic confirmation of an SOD1 mutation and clinical ALS meeting El Escorial criteria. Participants were randomized 2:1 to receive tofersen 100 mg intrathecally or placebo, administered at weeks 0, 2, 4, and then monthly for a 28-week primary assessment period. A pre-specified subgroup with faster disease progression was designated as the primary analysis group.
The primary endpoint was change in ALSFRS-R score from baseline to week 28 in the faster-progression subgroup. Secondary endpoints included changes in CSF SOD1 protein levels, plasma NfL, slow vital capacity, and muscle strength.
What they found in VALOR
The primary endpoint was not met. In the faster-progression subgroup, ALSFRS-R change from baseline was −6.98 in the tofersen group versus −8.14 in the placebo group — a difference of 1.2 points that did not reach statistical significance (P = 0.97 for the primary endpoint analysis, which used a complex hierarchical model).
Biomarker results were dramatically different. Tofersen reduced CSF SOD1 protein by 35% from baseline versus a 2% increase in placebo (P < 0.001). Plasma NfL — a marker of neurological injury reflecting ongoing motor neuron loss — was reduced by 60% in the tofersen group versus an increase of 20% in placebo (P < 0.001). These biomarker changes are among the largest ever observed in an ALS clinical trial.
In the 52-week combined analysis including participants who crossed over from placebo to open-label tofersen, those who started tofersen early maintained a 3.5-point ALSFRS-R advantage over those who started treatment later (95% CI 0.4–6.7). Adverse events were common and included lumbar puncture–related effects; neurologic serious adverse events (including aseptic meningitis) occurred in 7% of tofersen recipients.
FDA approval and the biomarker precedent
In April 2023, the FDA granted accelerated approval for tofersen (Qalsody) for the treatment of ALS associated with SOD1 mutations. The approval was based on the reduction in plasma NfL as a surrogate endpoint reasonably likely to predict clinical benefit — not on the primary functional endpoint, which had not been met.
This approval set an important precedent: neurofilament light chain, a biomarker of neurological injury, was accepted as a basis for drug approval in ALS. This opens the regulatory pathway for future ALS and potentially PLS drugs to seek approval on biomarker grounds, provided the biomarker-to-clinical-outcome relationship can be established.
Open-label extension: functional benefit at 3 years
JAMA Neurology published long-term open-label extension (OLE) data in December 2025. At the 3-year mark, approximately 25% of participants who had received tofersen throughout the trial showed functional stabilization or functional improvement on ALSFRS-R — an outcome that is essentially never seen in ALS without treatment, where functional decline is universal and relentless.
Improvements were observed in grip strength and respiratory function (slow vital capacity) in a subset of participants. Plasma NfL levels continued to decrease or remain suppressed with ongoing treatment, consistent with continued reduction in neurological injury.
Real-world data from the German early access program (Lancet eClinicalMedicine, 2024) confirmed the trial findings in a multicenter observational cohort of 12-month SOD1-ALS patients treated outside the trial setting: sustained NfL reduction and slower ALSFRS-R decline were observed. A real-world cohort study in 7 slow-progressing SOD1-ALS patients showed a serum NfL reduction and ALSFRS-R of 36.2 versus an expected 28.7 — approximately 52% slower progression.
Why it matters
Tofersen is the proof of concept for genetic targeting in ALS. It demonstrates that an ASO delivered intrathecally can reduce the production of a toxic ALS protein, lower a validated biomarker of motor neuron injury, and — at least in the population that receives it early enough — produce functional stabilization over years.
The 25% stabilization rate at 3 years is not a cure. Most participants continued to decline. But in a disease where global functional decline has previously been considered inevitable, even a quarter of patients stabilizing is meaningful clinical evidence. It also identifies an important research question: what distinguishes patients who stabilize from those who continue to decline, and can that knowledge guide future treatment optimization?
Tofersen's approval on a biomarker basis is equally important for the broader field. The NfL precedent has opened a regulatory pathway that could accelerate development of other ALS therapies — including, potentially, PLS therapies — by allowing approval based on biomarker suppression rather than requiring full demonstration of functional benefit in trials.
PLS relevance
Tofersen is specifically for SOD1-ALS — a genetic form of the disease caused by SOD1 mutations. PLS does not have a known equivalent genetic driver. Adult-onset sporadic PLS, which is the most common form, does not involve SOD1 mutations in most patients. Tofersen is not applicable to PLS patients as a therapy.
The relevance is conceptual and precedent-setting: the ASO development path, the biomarker approval framework, and the long-term open-label extension methodology are all models that future PLS drug development could adopt. If a PLS-enriched genetic variant were identified, the tofersen development path provides a blueprint.
How this connects
Tofersen is the most advanced targeted ALS therapy and represents the current ceiling of what gene-targeting approaches have achieved in ALS. For the foundational drug that preceded it, see Riluzole Original Trials. For how biomarkers like NfL are being integrated into trial design and regulatory decisions, see Biomarker Research. The full ALS drug pipeline context is in Drug Trial Research.
Citation
Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. New England Journal of Medicine. 2022;387:1099–1110. doi:10.1056/NEJMoa2204705. FDA accelerated approval: April 2023. OLE data: JAMA Neurology, December 2025.