VALOR
(2022)Objective
To evaluate the efficacy and safety of intrathecally administered antisense oligonucleotide tofersen in patients with ALS associated with SOD1 mutations
Study Summary
• Clear target engagement: 29% reduction in CSF SOD1 and 60% reduction in plasma neurofilament light chains with tofersen
• Combined 52-week analysis suggested potential benefit for early vs delayed tofersen initiation (ALSFRS-R difference 3.5 points)
Intervention
Tofersen 100mg intrathecal injection (8 doses over 24 weeks) vs placebo
Inclusion Criteria
Adults with weakness attributable to ALS and confirmed SOD1 mutation
Study Design
Arms: Tofersen 100mg intrathecal vs placebo (artificial CSF), 2:1 randomization
Patients per Arm: 72 tofersen, 36 placebo (108 total); primary analysis in faster-progression subgroup: 39 tofersen, 21 placebo
Outcome
• CSF SOD1: 29% reduction vs 16% increase (ratio 0.62, 95% CI 0.49-0.78)
• Neurologic SAEs in 7% of tofersen recipients
Bottom Line
Tofersen demonstrated clear target engagement with significant reductions in CSF SOD1 protein and plasma neurofilament light chains, but did not significantly improve clinical endpoints at 28 weeks. Combined analysis at 52 weeks comparing early-start vs delayed-start cohorts suggested potential clinical benefit with earlier treatment initiation, though these results require cautious interpretation due to lack of multiplicity adjustment.
Major Points
- Primary endpoint not met: ALSFRS-R change at 28 weeks was -6.98 with tofersen vs -8.14 with placebo (difference 1.2 points, p=0.97)
- Clear target engagement demonstrated: CSF SOD1 reduced by 29% with tofersen vs 16% increase with placebo
- Plasma neurofilament light chains reduced by 60% with tofersen vs 20% increase with placebo
- 88% of participants entered the open-label extension (95 of 108)
- At 52 weeks, early-start cohort showed -6.0 point ALSFRS-R change vs -9.5 in delayed-start cohort (difference 3.5 points, 95% CI 0.4-6.7)
- Neurologic serious adverse events occurred in 7% of tofersen recipients (myelitis, aseptic meningitis, lumbar radiculopathy, increased intracranial pressure, papilledema)
- 42 SOD1 mutations represented across 108 participants
- Trial included 16 participants with p.Ala5Val mutation (aggressive phenotype)
- Baseline imbalances existed: neurofilament light chains 15-25% higher and ALSFRS-R decline faster in tofersen group
- Study may have been underpowered due to slower-than-projected disease progression in placebo group
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled trial with open-label extension
- Randomization
- Yes
- Blinding
- Double-blind. Participants, investigators, and site staff remained blinded during extension phase to original VALOR assignments. Tofersen and placebo (artificial CSF) administered via identical intrathecal injection.
- Sample Size
- 108
- Follow-up
- 28 weeks (randomized phase); 52 weeks (combined analysis); ongoing extension up to 236 weeks
- Centers
- 32
- Countries
- United States, Canada, United Kingdom, Germany, Italy, Belgium, Japan, France, Netherlands, Australia
Primary Outcome
Definition: Change from baseline to week 28 in ALSFRS-R total score (range 0-48, higher = better function) in faster-progression subgroup, analyzed using joint rank test
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -8.14 (adjusted mean change) | -6.98 (adjusted mean change) | - (-3.2 to 5.5 (for difference)) | 0.97 (joint rank test) |
Limitations & Criticisms
- Primary endpoint not achieved - no significant clinical benefit demonstrated at 28 weeks
- Baseline imbalances: neurofilament light chains 15-25% higher and ALSFRS-R decline faster in tofersen group
- Study may have been underpowered due to slower-than-projected disease progression in placebo group (3x slower than anticipated)
- Prognostic criteria for faster/slower progression using SOD1 mutation type and prerandomization ALSFRS-R slope may not be consistently prognostic over short trial periods
- Combined analysis at 52 weeks not adjusted for multiplicity - no definitive conclusions can be drawn
- ~20% missing data requiring imputation in combined analysis
- VALOR results were known at time of combined analysis, potentially introducing bias
- Short 28-week duration may be insufficient to detect clinical benefit
- CSF pleocytosis in 58% of tofersen recipients raises questions about inflammatory response
- Neurologic serious adverse events (myelitis, meningitis) in 7% of recipients - mechanism unclear
- Relationship between CSF pleocytosis/elevated protein and myelitis not established
- Heterogeneous population with 42 different SOD1 mutations makes interpretation difficult
- Intrathecal administration via repeated lumbar punctures creates burden and procedural complications
Citation
N Engl J Med 2022;387:1099-1110