Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial

Abstract

Background: Spinal cord injury (SCI) causes neural disconnection and persistent neurological deficits, so axon sprouting and plasticity might promote recovery. Soluble Nogo-Receptor-Fc decoy (AXER-204) blocks inhibitors of axon growth and promotes recovery of motor function after SCI in animals. This first-in-human and randomised trial sought to determine primarily the safety and pharmacokinetics of AXER-204 in individuals with chronic SCI, and secondarily its effect on recovery.

Methods: We conducted a two-part study in adults (aged 18-65 years) with chronic (>1 year) cervical traumatic SCI at six rehabilitation centres in the USA. In part 1, AXER-204 was delivered open label as single intrathecal doses of 3 mg, 30 mg, 90 mg, or 200 mg, with primary outcomes of safety and pharmacokinetics. Part 2 was a randomised, parallel, double-blind comparison of six intrathecal doses of 200 mg AXER-204 over 104 days versus placebo. Participants were randomly allocated (1:1) by investigators using a central electronic system, stratified in blocks of four by American Spinal Injury Association Impairment Scale grade and receipt of AXER-204 in part 1. All investigators and patients were masked to treatment allocation until at least day 169. The part 2 primary objectives were safety and pharmacokinetics, with a key secondary objective to assess change in International Standards for Neurological Classification of SCI (ISNCSCI) Upper Extremity Motor Score (UEMS) at day 169 for all enrolled participants. This trial is registered with ClinicalTrials.gov, NCT03989440, and is completed.

Findings: We treated 24 participants in part 1 (six per dose; 18 men, six women), and 27 participants in part 2 (13 placebo, 14 AXER-204; 23 men, four women), between June 20, 2019, and June 21, 2022. There were no deaths and no discontinuations from the study due to an adverse event in part 1 and 2. In part 2, treatment-related adverse events were of similar incidence in AXER-204 and placebo groups (ten [71%] vs nine [69%]). Headache was the most common treatment-related adverse event (five [21%] in part 1, 11 [41%] in part 2). In part 1, AXER-204 reached mean maximal CSF concentration 1 day after dosing with 200 mg of 412 000 ng/mL (SD 129 000), exceeding those concentrations that were efficacious in animal studies. In part 2, mean changes from baseline to day 169 in ISNCSCI UEMS were 1·5 (SD 3·3) for AXER-204 and 0·9 (2·3) for placebo (mean difference 0·54, 95% CI -1·48 to 2·55; p=0·59).

Interpretation: This study delivers the first, to our knowledge, clinical trial of a rationally designed pharmacological treatment intended to promote neural repair in chronic SCI. AXER-204 appeared safe and reached target CSF concentrations; exploratory biomarker results were consistent with target engagement and synaptic stabilisation. Post-hoc subgroup analyses suggest that future trials could investigate efficacy in patients with moderately severe SCI without prior AXER-204 exposure.

Funding: Wings for Life Foundation, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, National Institute on Drug Abuse, and ReNetX Bio.

Figure 1.. Enrollment and Randomization of Participants

Diagram reflects the disposition of all individuals screened and enrolled in each part of the study.

Figure 2.. Upper Extremity Motor Score from Parts 1 and 2.

(A) Change from baseline in bilateral UEMS of the ISNCSCI examination is plotted for part 1. Bars reflect mean with ± 95% CI for indicated individuals. (B) Change from baseline in bilateral UEMS of the ISNCSCI examination by mixed-effects model for repeated measures (MMRM) analysis for part 2 groups. Figure shows least squares mean ± 95% CI for n =14 for AXER-204 and n=13 for placebo. Baseline was defined as the last non-missing value before the first dose of study treatment. By MRMM, non-significant.

Figure 3.. Secondary, Exploratory and Subgroup Efficacy Measures from Part 2.

(A) Change from baseline in bilateral GRASSP Prehension Performance score by mixed-effects model for repeated measures (MMRM) analysis for part 2 groups. Figure shows least squares mean ± 95% CI for n =14 for AXER-204 and n=13 for placebo. By MRMM, non-significant. (B) Change from baseline in SCIM III self-care by mixed-effects model for repeated measures (MMRM) analysis for part 2 groups. Figure shows least squares mean ± 95% CI for n =14 for AXER-204 and n=13 for placebo. By MRMM, non-significant. (C) Patient Global Impression of Change (PGIC) from baseline to Day 169 for part 2 groups. (D) Change from baseline in bilateral Pin Prick sensory score of the ISNCSCI examination by mixed-effects model for repeated measures (MMRM) analysis for part 2 groups is plotted. The least squares mean ± 95% CI is plotted for n =14 for AXER-204 and n=13 for placebo. By MRMM, non-significant. (E) Preplanned subgroup analysis for BCD participants of change in bilateral UEMS from the ISNCSCI examination. The least squares mean ± 95% CI is plotted for n=8 for AXER-204 and n=8 for placebo. By MRMM, non-significant. (F) Preplanned subgroup analysis for participants not enrolled in part 1 of change in bilateral UEMS from the ISNCSCI examination. The least squares mean ± 95% CI is plotted for n=9 for AXER-204 and n=9 for placebo. By MRMM, non-significant. (G) For BCD participants not enrolled in part 1, a post hoc analysis of change from baseline in bilateral UEMS from ISNCSCI examination. Data are arithmetic mean ± 95% CI for n=6 for AXER-204 and n=5 for placebo. By repeated measures ANOVA, time*group (P = 0.026), time (P = 0.032), and group (P = 0.072). (H) For BCD participants not enrolled in part 1, a post hoc analysis of change from baseline in total MS from ISNCSCI examination. Data are arithmetic mean ± 95% CI for n=6 for AXER-204 and n=5 for placebo. By repeated measures ANOVA, non-significant. (I) For BCD participants not enrolled in part 1, a post hoc analysis of change from baseline in GRASSP Prehension Performance and total MS of the ISNCSCI examination. Data are arithmetic mean ± 95% CI for n=6 for AXER-204 and n=5 for placebo. By repeated measures ANOVA, non-significant.

Figure 4.. CSF Biomarker Changes Induced by AXER-204.

(A) Protein composition by unbiased mass spectrometry-based proteomics for all part 1 CSF samples. 685 proteins were identified with at least two peptides mapped. Values for Day 1 samples are normalized by Day 0 from the same individual receiving 200 mg dose. For each identified protein, the -log10(P value) is plotted as a function of the log2(Fold Change), and the red dots reflect those for which |log2(Fold Change)| >0.9 and False Discovery Rate P value <0.05 corrected by Benjamini-Hochberg step-down (Q=12%, and uncorrected P value of 0.01). The gray dots reflect unidentified proteins that did not meet these thresholds. (B) Heatmap of protein levels across dose and time, showing values for up-regulated or down-regulated proteins meeting the same cutoffs as in A for 200 mg Day 1 dose are illustrated. For each protein, the values were normalized to the pre-dose value as baseline. Each box represents the average from 6 individual samples, and the intensity of the color is a linear reflection of the fold change from Day 0. (C) Gene set enrichment of proteins significantly down-regulated or up-regulated by AXER-204 from A and B, analyzed by ClueGo in Cytoscape. Gene Ontology term clusters for either Gene Ontology Biological Function or Gene Ontology Cellular Compartment are shown, and Bonferroni-corrected P value for enrichment is plotted. (D, E) Quantitation of APP level in CSF from immunoblots as a function of time after 200 mg (D) or of dose at Day 1 (E). Data are normalized by Day 0 values from the same individual, graphed as mean ± SEM. To compare the effect of AXER-204 as a function of time, data were analyzed by repeated measure ANOVA with a mixed effects model versus Day 0. D1, P=0.0001 To assess AXER-204 as a function of dose, a Kruskal-Wallis test versus the 3 mg values was used. P values <0.05 are plotted. D1, P=0.0001; D3, P=0.28; D7 P=0.0032, D28, P=0.65; 30 mg, >0.99; 90 mg, P=0.028; 200 mg, P=0.0026. Each dot represents a different CSF sample.