Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients

Abstract

Introduction/aims: We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.

Methods: Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double-blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the interleukin 6 receptor (IL-6R) gene.

Results: Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P < .001). CSF CRP reduction (-1.8-fold relative change, P = .01) was associated with IL-6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.

Discussion: Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL-6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL-6R C allele. These results warrant further study in ALS patients where IL-6R genotype and CRP levels may be useful enrichment biomarkers.

Trial registration: ClinicalTrials.gov NCT02469896.

Keywords: C-reactive protein; amyotrophic lateral sclerosis; interleukin-6; microglia; tocilizumab.

© 2021 Wiley Periodicals LLC.

Figures

Figure 1.

CONSORT diagram.

Figure 2.

Plasma (A–C, logarithmic scale) and cerebrospinal fluid (CSF; D–F, linear scale) trajectories of select cytokines and proteins. Adjusted mean estimates and their 95% confidence intervals are plotted by treatment group and visit. Concentrations of the inflammatory indicator C-reactive protein (CRP; A, D) are reduced, while interleukin 6 (IL-6; B, E) and its soluble receptor (sIL-6R; C, F) levels are significantly increased in plasma and CSF in participants treated with tocilizumab. Results are expressed as mean concentration ± 95% CI. Statistical analysis to determine significant differences was performed as described in the methods. Adjusted P-values for differences between participants treated with tocilizumab versus placebo at 8 weeks (a time reflective of treatment effect) and 16 weeks (a time when treatment effects are reduced), and differences between the two groups from baseline to the average of weeks 4–16, were all P<0.001 for plasma CRP, IL-6, and sIL-6R. The differences between tocilizumab versus placebo at 8 weeks were statistically significant for CSF measurements ([adjusted] CRP, P=0.01; IL-6, P<0.001; sIL-6R, P<0.001). For all measures there were no differences from baseline to weeks 4–16 in placebo-treated individuals (plasma unadjusted p–values : CRP, P=0.94; IL-6, P=0.72; IL-6R, P=0.93; CSF: CRP, P=0.41; IL-6, P=0.26; sIL-6R, P=0.70). Changes were consistently observed in tocilizumab-treated individuals (plasma unadjusted p–values: CRP, P<0.001; IL-6, P<0.001; sIL-6R, P<0.001; CSF unadjusted p–values: CRP, P<0.001; IL-6, P<0.001; sIL-6R, P<0.001).

Figure 3.

Cerebrospinal fluid (CSF) trajectories of select cytokines and proteins. Adjusted mean estimates and their 95% confidence intervals are plotted by treatment group, IL6R Asp358Ala genotype, and visit. (A) Individuals who inherit the IL6R Ala358 allele exhibited reductions in CSF C-reactive protein (CRP). (B) Increases in interleukin 6 (IL-6) or (C) soluble IL-6 receptor did not appear to be influenced by the allele’s presence. Results are expressed as mean concentration ± 95% CI. Adjusted P-values for differences from baseline to week 8 between participants treated with tocilizumab versus placebo are shown. There were no differences from baseline to week 8 in any placebo-treated individuals for all measures and genotypes. Reductions in CSF CRP were observed in tocilizumab-treated AC and CC, but not AA individuals, suggesting influence by the allele (tocilizumab vs placebo X #C 8-wk change, unadjusted P=0.03). However, its significance was not maintained after correction for multiple comparisons (adjusted P=0.74). Presence of the Ala358 allele had no influence on tocilizumab-induced increase in IL-6 or sIL-6R (unadjusted IL-6 #C, P=0.64; sIL-6R #C, P=0.66).