VALOR-OLE
(2025)Objective
Evaluate the long-term effects of early-start versus placebo/delayed-start tofersen on function, strength, survival, and biomarkers in adults with SOD1-ALS, integrating the 28-week VALOR phase 3 trial with its open-label extension (median 4.9 years of follow-up).
Study Summary
• Faster-progressing (high-NfL) subgroup: median time to death/permanent ventilation 253.6 vs 76.0 weeks (early vs delayed), HR 0.47 (0.19–1.18).
• Serious neurologic AEs in 8.7% — myelitis 3.9%, papilledema 2.9%, aseptic meningitis 1.9%; most reversible with standard care.
Intervention
Intrathecal tofersen 100 mg (SOD1-targeting antisense oligonucleotide); dosing every 4 weeks after a loading phase
Inclusion Criteria
Adults ≥18 years with weakness attributable to ALS and a confirmed pathogenic or likely pathogenic SOD1 variant
Study Design
Arms: Early-start tofersen (treated in VALOR + OLE) vs placebo/delayed-start tofersen (placebo in VALOR, tofersen from OLE entry ~6 months later)
Patients per Arm: Early start 72; placebo/delayed start 36 (ITT N=108; 95 entered OLE)
Outcome
• %-predicted SVC 148-week change −13.8 vs −18.1 (LSM diff 4.3, 95% CI −6.6 to 15.2).
• HHD megascore change −0.38 vs −0.43 (LSM diff 0.06).
• Plasma NfL reductions ~67%/64% sustained at week 148; total CSF SOD1 reduced 21%/25%.
• Time to death or PV: ITT HR 0.64 (0.28–1.46); time to death HR 0.52 (0.20–1.36); time to death/PV/withdrawal HR 0.61 (0.31–1.18).
• Faster-progressing NfL subgroup: ~3.4-year extension of event-free survival with early start.
• Safety: serious neurologic AEs in 8.7% (myelitis 3.9%, papilledema 2.9%, aseptic meningitis 1.9%); 26.9% discontinued for any AE; 21.2% died (consistent with ALS natural history).
Clinical Question
In adults with SOD1-ALS, does earlier initiation of intrathecal tofersen (vs ~6-month delayed start) slow long-term decline in function, strength, and quality of life and reduce risk of death or permanent ventilation?
Bottom Line
Over a median 4.9-year follow-up, earlier tofersen was associated with numerically less decline in ALSFRS-R, SVC, HHD strength, and quality-of-life measures and substantial sustained reductions in plasma neurofilament light chain; in the faster-progressing (high-NfL) subgroup, early start extended event-free survival by ~3.4 years, supporting use of tofersen as disease-modifying therapy for SOD1-ALS and earlier initiation in symptomatic disease.
Major Points
- Integrated ITT analysis of phase 3 VALOR (28 weeks, 2:1 tofersen 100 mg vs placebo) and its open-label extension; 95/108 entered OLE; median opportunity for follow-up 4.9 years (range 3.6–5.4 years).
- Plasma NfL fell ~67% (early-start) and ~64% (placebo/delayed-start) from baseline and stayed suppressed through week 148; total CSF SOD1 protein fell ~21%–25%, confirming sustained target engagement.
- At 148 weeks, early start vs placebo/delayed start showed numerically less decline on ALSFRS-R (−9.9 vs −13.5), %-predicted SVC (−13.8 vs −18.1), HHD megascore (−0.38 vs −0.43), and ALSAQ-5 (17.0 vs 22.5) — all favoring early start but not statistically significant on ANCOVA (joint rank test for ALSFRS-R P=.05).
- Compared with ALS natural history (expected ~22–34-point ALSFRS-R decline over 148 weeks), both groups declined substantially less, consistent with disease-progression slowing in both arms.
- 21%–27% of early-start participants improved on function/strength measures at 148 weeks; simulation against the dexpramipexole EMPOWER natural-history model estimated the probability of a 27.3% HHD improver rate at 1 year in untreated patients to be 0% (P<.001).
- Event-free survival in the ITT population: HR for death or permanent ventilation 0.64 (0.28–1.46); HR for death 0.52 (0.20–1.36); HR for death/PV/withdrawal-for-progression 0.61 (0.31–1.18). In the high-NfL faster-progressing subgroup, early start extended median time to death/PV by ~3.4 years (253.6 vs 76.0 weeks) and median time to death by ~2.65 years.
- Safety: 103/104 (99%) had any AE; 55.8% had a serious AE; 21.2% had a fatal-outcome event (driven by ALS progression); 26.9% discontinued for AE. Serious neurologic AEs in 8.7% (myelitis 3.9%, papilledema/raised ICP 2.9%, aseptic/chemical meningitis 1.9%) — all reversible with standard care; only 1 myelitis and 1 chemical meningitis led to drug discontinuation.
- Findings supported FDA acceptance of NfL as a surrogate biomarker reasonably likely to predict clinical benefit in SOD1-ALS; tofersen is approved in the US, EU, China, Japan and others, and European Academy of Neurology guidelines recommend it as first-line therapy for progressive SOD1-ALS.
Study Design
- Study Type
- Phase 3 randomized, double-blind, placebo-controlled trial (VALOR) with prospectively integrated open-label extension (OLE)
- Randomization
- Yes
- Blinding
- Double-blind in VALOR (28 weeks); OLE personnel, participants, and caregivers remained blinded to VALOR randomization assignment
- Sample Size
- 108
- Follow-up
- Median opportunity for follow-up 4.9 years (range 3.6–5.4 years); main efficacy analysis at week 148; survival analyses through week 276
- Centers
- 32
- Countries
- USA, UK, Canada, Japan, Italy, Belgium, Germany, France, Spain, Netherlands
Primary Outcome
Definition: Integrated 148-week change from baseline in ALSFRS-R total score (early-start vs placebo/delayed-start)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −13.5 points | −9.9 points | - | - |
Limitations & Criticisms
- Small ITT sample (N=108) — analyses were not powered to detect statistically significant treatment differences on clinical outcomes; reported between-group comparisons are numerical/exploratory.
- All participants had the opportunity to receive tofersen from week 28 onward, so the long-term comparison reflects only a ~6-month timing offset rather than treatment vs no treatment.
- Substantial dropout/death by OLE end (only 46/108 completed), and time-to-event medians not estimable in the ITT population — extension-of-survival estimates rely on the faster-progressing NfL subgroup.
- SOD1 variant heterogeneity (42 unique variants) limits subgroup precision and generalization across SOD1 genotypes.
- Funded and largely analyzed by Biogen; multiple authors are Biogen employees/shareholders, with the sponsor involved in design, monitoring, statistical analysis, interpretation, and drafting.
- Comparisons to natural history rely on external cohorts (PRO-ACT, dexpramipexole/EMPOWER) and modeling assumptions; no contemporaneous untreated control beyond 6 months.
- Multiple imputation and joint-rank test results were positive only as alternative analyses (ALSFRS-R P=.05 for JRT vs P=.14 for ANCOVA), highlighting sensitivity to analytic choice.
Citation
JAMA Neurol. 2025 Dec 22;83(2):115-125. doi:10.1001/jamaneurol.2025.4946