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Summary
ALS (amyotrophic lateral sclerosis) has long been one of the most devastating and treatment-resistant diseases in medicine. That is beginning to change. The FDA approval of tofersen for SOD1-ALS in 2023 — the first precision ALS therapy — established that targeting the genetic cause of ALS can slow progression and preserve function. In 2026, the field is pushing further: pre-symptomatic treatment trials, intrathecal ASOs for multiple ALS genes, and the first serious evaluation of whether treating before motor neuron loss begins can preserve neurological function indefinitely.
Tofersen: The First Precision ALS Medicine
SOD1-ALS accounts for approximately 2% of all ALS cases (~200–300 people diagnosed per year in the US) but has been the focus of intense research because it has the clearest molecular target. Mutations in the SOD1 gene cause misfolded SOD1 protein that is toxic to motor neurons.
Tofersen (Qalsody, Biogen) is an antisense oligonucleotide (ASO) that binds to SOD1 mRNA and triggers its degradation, reducing the production of toxic SOD1 protein. In the VALOR Phase 3 trial, tofersen did not achieve its primary endpoint of slowing functional decline at 28 weeks in the full population — but did show significant benefit in the fastest-progressing patients. Extension data showed that patients who started tofersen earlier had better functional outcomes, and plasma and CSF neurofilament light chain (NfL) — a biomarker of neurodegeneration — decreased dramatically (>50%) with treatment. FDA approved tofersen under accelerated approval in April 2023 based on NfL reduction as a surrogate biomarker.
ATLAS: Treating ALS Before Symptoms Begin
The ATLAS trial (Biogen) is one of the most ambitious ALS trials ever conducted. It enrolls asymptomatic adults who carry pathogenic SOD1 mutations and have elevated plasma NfL — indicating early neurodegeneration is already underway before any symptoms appear. Participants receive tofersen injections intrathecally every few months.
The hypothesis is that if motor neuron death can be halted before symptoms manifest, patients may never develop functional ALS — or at minimum, their disease onset can be significantly delayed. Genetic testing of family members of SOD1-ALS patients is essential to identify trial candidates. ATLAS is actively enrolling in 2026; preliminary NfL data has been encouraging, with participants' plasma NfL normalizing toward age-matched controls. Full clinical outcome data — whether symptom onset is delayed — will require years of follow-up.
Extending ASOs to Other Genetic ALS Subtypes
SOD1 is one of over 25 genes implicated in familial ALS. ASO strategies are being developed for multiple other genetic subtypes:
C9orf72 ALS/FTD: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of ALS, accounting for ~40% of familial cases and ~10% of sporadic ALS. Toxic RNA foci and dipeptide repeat proteins (DPRs) produced from the expanded repeat are believed to be pathogenic. Wave Life Sciences and Novartis are advancing ASOs targeting C9orf72 in Phase 1/2 trials. The challenge is whether reducing C9orf72 expression (which has normal cellular functions) is safe alongside reducing pathogenic transcripts.
FUS-ALS: FUS mutations cause a particularly aggressive early-onset ALS. Ionis Pharmaceuticals has developed ION363, an intrathecal ASO targeting FUS mRNA. The drug received Expanded Access approval after a single compassionate-use patient — Jaci Hermstad — showed stabilized progression, prompting an expedited Phase 1/2 trial (FUSION) that is now actively enrolling.
Ataxin-2 lowering: Antisense targeting of ataxin-2, a protein that stabilizes TDP-43 aggregates (the pathological hallmark of ~97% of all ALS), is in Phase 1 trials. This approach could have relevance to both familial and sporadic ALS.
Stem Cell Approaches and Neuroprotection
Stem cell therapy for ALS has had a difficult history — many early studies were underpowered or used inadequate delivery methods. Neuroglia Therapeutics and BrainStorm Cell Therapeutics (NurOwn) have conducted Phase 2/3 trials with mesenchymal stem cells engineered to secrete neurotrophic factors. NurOwn's Phase 3 trial failed its primary endpoint, but subgroup analyses suggested benefit in less-advanced patients, prompting modified trials in earlier-stage disease.
Relyvrio (sodium phenylbutyrate/ursodoxicoltaurine, now known as AMX0035 or Albrioza in Canada) was approved by the FDA in 2022 based on a Phase 2 trial showing 25% slower functional decline. A Phase 3 confirmatory trial (PHOENIX) failed to confirm benefit, and the manufacturer withdrew the drug from the US market in late 2023 — a significant setback but a reminder of the importance of confirmatory trials.
Biomarker Advances and AI-Driven Trial Design
Plasma neurofilament light chain (NfL) is now established as a pharmacodynamic biomarker in ALS trials — it decreases with effective treatment and tracks disease progression. This has enabled smaller, faster trials: instead of waiting for functional decline (which requires hundreds of patients followed for 18 months), a trial can assess NfL reduction at 12 weeks in 40–60 patients to determine whether a drug engages its target and potentially slows neurodegeneration.
AI-driven platforms (Prize4Life's PRO-ACT database, Answer ALS project) are analyzing multi-omic data from thousands of ALS patients to identify subgroups, predict progression rates, and match patients to trials most likely to show benefit. Digital biomarkers from wearables are being validated as remote outcome measures, reducing the burden of frequent clinical site visits for patients with progressive disability.
Key Takeaways
- Tofersen (Qalsody) is FDA-approved for SOD1-ALS and is the first precision medicine for any ALS subtype; it reduces plasma NfL by >50%.
- The ATLAS trial is treating asymptomatic SOD1 mutation carriers before symptoms appear — possibly delaying or preventing ALS onset entirely.
- ASO programs for C9orf72 and FUS-ALS are in Phase 1/2 trials, following the tofersen proof-of-concept for gene-targeted ALS therapy.
- Plasma NfL as a surrogate biomarker is accelerating ALS trial timelines and enabling smaller, faster proof-of-concept studies.
- AI-driven patient stratification and digital outcome measures are improving trial efficiency for a disease where patient burden is high.