Nanocrystalline gold (CNM-Au8): a novel bioenergetic treatment for ALS

KEYWORDS:

• ALS
• CNM-Au8
• neurofilament
• MUNIX

1. Editorial

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the human motor neurons, with a median survival of 3–5 years [1,2]. Four disease-modifying therapies have been approved by the US Food and Drug Administration (FDA), namely riluzole, edaravone, AMX0035 (Relyvrio), and tofersen (SOD-1 antisense oligonucleotide), while only riluzole has been approved by the European Medicines Agency. Overall, these disease-modifying therapies exhibit marginal efficacy and survival benefit with effectiveness evident in a select cohort of patients [3–7]. Additionally, there have been concerns about the longer-term therapeutic efficacy of edaravone, particularly in a broader population of ALS patients [8]. Despite advances in our understanding of ALS pathophysiology, genetics, and disease heterogeneity, there remains an exigent need for the development of effective disease-modifying ALS treatments. Developing novel therapeutic approaches, along with innovative trial designs that utilize objective outcome endpoints [1], will promote the development of more effective therapies for ALS [9].

Abnormalities of energy metabolism have been implicated as a crucial pathophysiological process in ALS [10]. Specifically, abnormal energy homeostasis has been reported as an early or presymptomatic feature in ALS, resulting in increased energy expenditure and an adverse prognosis [10]. Additionally, impaired energy metabolism impacts oxidative phosphorylation and glycolysis, resulting in cellular dysfunction and neurodegeneration [11]. Addressing energy metabolism deficits may represent a novel approach to alleviate impaired proteostasis and could further serve as a potential therapeutic target [10].

Nanocrystalline gold (CNM-Au8) is administered as an aqueous suspension of clean surface gold that provides energetic support to neuronal cells in the central nervous system [12]. CNM-Au8 catalyzes the oxidation of nicotinamide adenine dinucleotide hydride (NADH) to the critical energetic co-factor NAD⁺ [12]. Of relevance, NAD⁺ and NADH serve as an essential redox couple for ATP generation, oxidative phosphorylation, and glycolysis [13]. Additionally, NADH oxidation drives cellular respiratory and metabolic processes [12], redressing potential energy imbalances in ALS.

The potential of CNM-Au8 as a treatment of ALS was investigated in several in vitro and in vivo models [12]. Specifically, CNM-Au8 was associated with a dose-dependent increase in motor neuron survival, with improvement in mitochondrial membrane potential, and a reduction in TAR DNA-binding protein 43 (TDP-43) protein aggregation in rodent spinal neurons co-cultured with glial cells and excitotoxic levels of glutamate. Additionally, CNM-Au8 increased the survival of C9ORF72 patient-derived cortical neurons and resulted in a dose-dependent increase in human motor neuron survival co-cultured with SOD1^A4V ALS-patient-derived astrocytes. In transgenic ALS mouse model (SOD1^G93A) studies, CNM-Au8 improved survival and motor function but was not associated with adverse effects. These preclinical findings of potential efficacy and safety supported the translation of CNM-Au8 into clinical trials.

In the current issue of Expert Opinion on Investigational Drugs, the pharmacodynamics, pharmacokinetics, and potential clinical efficacy of CNM-Au8 are reviewed, particularly in relation to ALS. Clinical efficacy and safety of CNM-Au8 were assessed in a phase 2, randomized, double-blind, placebo-controlled trial and open-label extension clinical trial RESCUE-ALS (NCT04098406 and NCT05299658) [14], as well as through the Healey adaptive platform trial facility [15]. RESCUE-ALS and its long-term open-label extension (OLE) study recruited a total of 45 ALS patients that were randomized 1:1 to receive 30 mg of CNM-Au8 or placebo over a 36-week period. Innovative trial design features included neurophysiological biomarkers as the primary endpoint, specifically the mean percent change in the summed motor unit number index (MUNIX) score. Assessment of forced vital capacity (FVC) served as secondary outcome measures, while ALS disease progression, the ALS Functional Rating Scale (ALSFRS-R) score, and quality of life (ALSSQOL-SF) were incorporated as exploratory outcome measures. All-cause mortality of patients that were originally randomized to the active group were compared to those originally randomized to placebo, from baseline through to at least 12 months following the last-patient last-visit (LPLV) of the double-bind period.

A 55% absolute risk reduction in the rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of noninvasive ventilatory support, or gastrostomy tube placement, was evident in the CNM-Au8-treated group (p = 0.0125). Additionally, the proportion of ALS patients with a ≥ 6-point decline in the total ALSFRS-R score was reduced in the CNM-Au8-treated group (30% absolute risk reduction, p = 0.035) with accompanying improvement in quality-of-life (p = 0.0177). The potential clinical benefits evidenced by exploratory endpoints in the RESCUL-ALS trial were accompanied by a significant increase in survival in the OLE, as indicated by a 60% reduction in all-cause mortality in the CNM-Au8-treated cohort [hazard ratio = 0·408 (95% CI: 0·166 to 1·001, log-rank p = 0·0429) through to 12-month LPLV. CNM-Au8 was well tolerated, and no safety signals were observed. While there were no significant differences in the primary or secondary endpoints at 36 weeks, there was a 45% reduction in the mean percent change of the summed MUNIX score (P = 0.074), suggesting that CNMAu8 exerted neuroprotective effects on the lower motor neurons in ALS. The clinical benefits of CNMAu8 appeared to be more prominent in spinal-onset ALS patients.

Preliminary results of the Phase 2 Healey ALS Platform trial indicate that CNM-Au8 treatment did not slow ALSFRS-R change following 24 weeks of treatment [16], although a significant reduction in neurofilament light chain (NfL) levels was subsequently identified (least-squares [LS] mean difference −0.100 ± 0.048; p = 0.040). The reduction in serum NfL levels was more prominent in ALS patients classified as fast progressors, defined as the baseline pretreatment ALSFRS-R slope > 0.45 (LS mean difference −0.144 ± 0.058, p = 0.014), definite or probable ALS diagnosis as per the El Escorial criteria (LS mean difference was −0.124 ± 0.054; p  = 0.023), and those with higher mortality risk, defined as baseline plasma NfL level above the median (LS mean difference −0.150 ± 0.068; p = 0.031). The absence of clinical benefits at 24 weeks could relate to a slower uptake and absorption of CNM-Au8, resulting in a prolonged subtherapeutic period before drug tissue concentrations reach a therapeutic level necessary to influence long-term survival and functional change.

Given that the totality of survival and time-to-event data, along with the effects on serum NfL levels, a robust biomarker of neurodegeneration in ALS [17], global initiatives are currently underway to progress to a phase-3 international multicentre clinical trial that is powered to investigate the clinical effects of CNMAu8 in ALS.

1.1. Expert opinion

There is an unmet need for more effective disease-modifying and neuroprotective therapies in ALS. CNM-Au8 represents a paradigm shift in the treatment of ALS [1], given the broad effects on energetic dysregulation, thereby impacting multiple pathophysiological processes in ALS, including an increase in cellular energy production, improved resistance to oxidative, mitochondrial, and excitotoxic stressors, as well as a reduction in protein aggregation, a key pathogenic mechanism in ALS. Preclinical cellular and transgenic mouse model studies have demonstrated the effectiveness of CNM-Au8 as indicated by prolonged survival, improved motor function, and evidence of neuroprotection. The comprehensive and important review encompassing the pharmacodynamics, pharmacokinetics, and potential clinical efficacy of CNM-Au8 highlights potential therapeutic utility in ALS.

While the initial phase 2 clinical trials (RESCUE-ALS and the Healey adaptive platform trial) did not reach clinical significance on primary endpoints, benefits were evident in a number of exploratory endpoints. Notably, CNM-Au8 was associated with a significant reduction in the rate of disease progression (55% absolute risk reduction) and improvement in long-term survival (60% reduction). These clinical effects were accompanied by a significant reduction in serum NfL levels, suggesting a putative neuroprotective effect of CNM-Au8. While these results are encouraging, the clinical efficacy of CNM-Au8 needs to be demonstrated in a large multicenter phase 3 study (RESORE-ALS).

Declaration of interests

S Vuvic and MC Kiernan are directors of companies that hold equity in Clene Nanomedicine. S Vuvic, MC Kiernan, and their respective institutions receive research funding support for the Rescue-ALS study from Clene Nanomedicine. MC Kiernan was Editor-in-Chief of the Journal of Neurology, Neurosurgery and Psychiatry (BMJ Publishers, UK).

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.