Amyotrophic lateral sclerosis remains rapidly progressive and ultimately fatal, but the last few years have brought real movement — particularly for genetically defined subgroups — along with an instructive lesson in how a "negative" trial can still change practice, and how an approved drug can later be withdrawn.
Tofersen (SOD1-ALS): approved despite a negative primary trial
Tofersen is an intrathecally administered antisense oligonucleotide that lowers SOD1 mRNA. In the Phase 3 VALOR trial, it missed its primary endpoint: the change in ALSFRS-R at week 28 in the faster-progressing subgroup was −6.98 with tofersen versus −8.14 with placebo (difference 1.2 points; 95% CI −3.2 to 5.5; P=0.97). But the biological effect was unmistakable — CSF SOD1 fell and plasma neurofilament light chain dropped by about 60% (versus a 20% rise with placebo). At 52 weeks, combining VALOR with its open-label extension, patients who started tofersen earlier declined less than those who started later (ALSFRS-R −6.0 vs −9.5; difference 3.5 points).
On the strength of that neurofilament effect, tofersen (Qalsody) received US accelerated approval in 2023 — the first therapy to target a genetic cause of ALS — with European approval following. Real-world cohorts confirm the neurofilament reduction and suggest slower progression, especially with early initiation. Adverse events include headache and back pain (from lumbar puncture) and, in around 7%, serious neurologic events such as myelitis, radiculitis, aseptic meningitis, and raised intracranial pressure with papilloedema. Tofersen is relevant only to SOD1-ALS, roughly 2% of cases.
Sodium phenylbutyrate–taurursodiol (Relyvrio/AMX0035): approved, then withdrawn
In the CENTAUR Phase 2 trial, this mitochondrial and endoplasmic-reticulum-stress modulator modestly slowed functional decline (ALSFRS-R −1.24 vs −1.66 points/month; difference 0.42). It was approved in 2022 — but the larger confirmatory Phase 3 PHOENIX trial failed to meet its endpoints, and the manufacturer voluntarily withdrew Relyvrio from the US and Canadian markets in April 2024. It should no longer be considered an option for new patients.
Edaravone: free-radical scavenger
Edaravone modestly slows functional decline, with the best evidence in early-stage patients meeting defined diagnostic criteria. It is available intravenously and as an oral formulation (Radicava ORS), which has eased administration. Real-world pharmacovigilance has flagged occasional serious events (hepatic dysfunction, thrombosis, cerebral events); caution is advised in renal impairment, and it is contraindicated with sulfite hypersensitivity.
What's new: gene-directed therapy beyond SOD1
The most striking recent signal comes from ulefnersen (jacifusen), an antisense oligonucleotide targeting FUS, in FUS-ALS — a rare, frequently young-onset form. In expanded-access use it has produced large reductions in neurofilament and, in individual patients, marked functional recovery, with one presymptomatic carrier remaining asymptomatic on treatment for years. Its pivotal Phase 3 FUSION trial completed enrollment in 2025, with results expected in 2026. Programs targeting C9orf72 and the axonal-stability gene STMN2 are also advancing.
| Therapy | Mechanism | Efficacy | Status |
|---|---|---|---|
| Tofersen | SOD1 antisense | Missed primary endpoint; strong biomarker effect; early-start benefit at 52 wk | Approved (US 2023, EU) for SOD1-ALS |
| Na phenylbutyrate–taurursodiol | Mitochondrial/ER-stress modulator | Modest Phase 2 benefit; Phase 3 failed | Withdrawn (2024) |
| Edaravone | Free-radical scavenger | Modest slowing, early disease | Approved; IV and oral |
| Ulefnersen (jacifusen) | FUS antisense | Striking individual responses | Phase 3 (FUSION), reading out ~2026 |
Further reading: VALOR (Miller et al., NEJM 2022); CENTAUR (Paganoni et al., NEJM 2020) and the Relyvrio withdrawal (PHOENIX, 2024); edaravone (Writing Group, Lancet Neurology 2017); ulefnersen expanded-access series in FUS-ALS (2025).