Evidence of brain target engagement in Parkinson's disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials

Abstract

Background: Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson's disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively.

Results: Brain metabolites were measured using 7-Tesla ³¹P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD⁺/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD⁺/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including β-ATP and phosphorylation potential across both cohorts.

Conclusions: Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.

Keywords: Brain energy metabolites; Catalytic gold nanotherapeutic; Drug development; Magnetic resonance spectroscopy; Multiple sclerosis; Neuroimaging; Parkinson’s Disease; Target engagement.

Fig. 1

Increased NAD⁺/NADH Brain Ratio in Both PD and MS Participants in the REPAIR Studies. (a-c) Pre-specified integrated analyses of REPAIR-MS and REPAIR-PD values of the primary endpoint, (a) change in brain NAD⁺/NADH ratio [mean change in ratio from baseline to end of study = 0.5891, + 10.4%, p = 0.0371 (paired t-test)], and secondary endpoints, (b) change in NAD⁺ fraction and change in NADH fraction after 12 + weeks of daily dosing of CNM-Au8 [mean change of NAD + fraction, 0.0093, + 1.1%, with a reciprocal change of NADH fraction, -0.0093, -1.1%; p = 0.0264 (paired t-test)]. (c) The REPAIR-MS trial protocol included a 6-week withdrawal of treatment following 12 weeks of dosing. After withdrawal of treatment, at week 18, a final ³¹P-MRS scan showed that NAD⁺/NADH ratio had returned to baseline levels. Bar graphs show mean ±95% CI; individual participant values at baseline (blue circles), end of study (green triangles), and 6 weeks post-treatment (black diamonds)

Fig. 2

ATP and Phosphorylation Potential Equilibration in REPAIR Clinical Trials. Pre-specified integrated analyses of REPAIR-MS and REPAIR-PD values of the exploratory endpoints, (a) Percent change in β-ATP from baseline to end-of-study and (b) Percent change in phosphorylation potential from baseline to end-of study, plotted against baseline values for β-ATP and phosphorylation potential, respectively. Individual values for REPAIR-PD participants (n = 13) are shown as light green triangles; individual values for REPAIR-MS participants are shown as dark green diamonds. Linear regression line (orange) and 95% CI (dashed curves) are shown