Tocilizumab ALS Safety Trial
(2021)Objective
To test safety, tolerability, and target engagement of tocilizumab (IL-6 receptor antagonist) in ALS patients with high inflammatory PBMC gene expression profiles
Study Summary
• Plasma CRP reduced by 88% with tocilizumab vs 4% increase with placebo (p<0.001)
• CSF CRP reduction associated with IL6R C allele genotype, suggesting potential for personalized therapy
Intervention
Tocilizumab 8mg/kg IV at weeks 0, 4, and 8 vs placebo
Inclusion Criteria
Age 18-75 years, possible/probable/definite ALS by El Escorial criteria, slow vital capacity ≥40% predicted, high inflammatory PBMC gene expression profile
Study Design
Arms: Tocilizumab 8mg/kg IV vs placebo (2:1 randomization)
Patients per Arm: 14 tocilizumab, 8 placebo (22 total)
Outcome
• Plasma CRP: -88% tocilizumab vs +4% placebo (-3.1-fold relative change, p=0.003)
• No differences in ALSFRS-R or clinical measures between groups
Bottom Line
Tocilizumab was safe and well tolerated in ALS patients with high inflammatory gene expression profiles. Treatment significantly reduced plasma CRP by 88% and CSF CRP by 1.8-fold relative to placebo, with CSF effects potentially dependent on IL6R Asp358Ala genotype. PBMC gene expression was not useful as a predictive or pharmacodynamic biomarker. These results warrant further study in ALS patients enriched for IL6R C allele carriers and elevated CRP levels.
Major Points
- First study to demonstrate tocilizumab safety and tolerability specifically in ALS patients
- Plasma CRP reduced by 88% in tocilizumab group vs 4% increase in placebo (-3.1-fold relative change, p=0.003)
- CSF CRP reduction of 1.8-fold relative to placebo (p=0.01 unadjusted), first demonstration of tocilizumab effect on CSF CRP
- CSF CRP reduction was greater in individuals with more IL6R C allele copies, suggesting genotype-dependent effects
- Plasma IL-6 increased 2.9-fold and plasma sIL-6R increased 3.4-fold with tocilizumab (expected pharmacodynamic effect)
- PBMC inflammatory gene expression (IL6, IL8, MMP1) was not a useful pharmacodynamic biomarker
- No clinical efficacy signal detected, but study was not powered for clinical outcomes
- IL6R C allele frequency of 0.50 in study population (higher than expected 0.37)
- Results support IL-6 trans-signaling as potential therapeutic target in ALS subpopulation
Study Design
- Study Type
- Phase 2, multicenter, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 22
- Follow-up
- 16 weeks
- Centers
- 5
- Countries
- United States
Primary Outcome
Definition: Safety (proportion experiencing treatment-emergent adverse events per MedDRA) and tolerability (completing all infusions and study visits). Secondary primary: proportion with ≥2-fold decline in ≥2 of 3 pro-inflammatory genes (IL6, IL8, MMP1)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Tolerability: 75% (6/8 completed). 1 severe AE (aspiration pneumonia). 2 withdrew consent. | Tolerability: 86% (12/14 completed). No severe AEs. 2 discontinued infusions (neutropenia, C. difficile colitis) but completed visits. | - | 0.60 (tolerability comparison) |
Limitations & Criticisms
- Very small sample size (n=22) limits statistical power for efficacy and subgroup analyses
- PBMC inflammatory gene expression profile was not useful as predictive or pharmacodynamic biomarker
- CSF CRP significance not maintained after correction for multiple comparisons (unadjusted p=0.01, adjusted p=0.22)
- CRP was not prespecified as selection criterion - in retrospect would have been more useful than PBMC gene expression
- Tocilizumab levels in CSF were not measured
- Study not powered to detect clinical effects
- Participants had slower-than-average disease progression (ALSFRS-R decline <3 points), making clinical benefit harder to detect
- Short treatment duration (8 weeks) and follow-up (16 weeks)
- Higher than expected IL6R C allele frequency (0.50 vs 0.37) may reflect selection bias from PBMC criteria
- Increased circulating IL-6 levels with treatment raise theoretical concern, though likely reflects altered catabolism rather than pathway upregulation
- Genotype-dependent CSF CRP effects were post-hoc and require confirmation
Citation
Muscle Nerve. 2021 September;64(3):309-320