Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

A Mechanism Underpinning the Bioenergetic Metabolism-Regulating Function of Gold Nanocatalysts.

Bioenergetic deficits are known to be significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the energy metabolism-regulating function of colloidal Au nanocrystals, referred to as CNM-Au8, that are synthesized electrochemically in the absence of surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and neurite network preservation across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic cofactor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized counterpart (NAD+ ), which promotes bioenergy production by regulating the intracellular level of adenosine triphosphate. Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. Photoexcited charge carriers and photothermal effect, which result from optical excitations and decay of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, are further harnessed as unique leverages to modulate reaction kinetics. As exemplified by this work, Au nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.

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.

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 ß-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.

Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.

Background: CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS). Methods: RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N = 45) were randomised 1:1 to receive 30 mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively. Findings: In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI: -11.9 to 27.3%, p = 0.43), total MUNIX score change (18.8, 95% CI: -56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI: -12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio = 0.408 (95% Wald CI: 0.166 to 1.001, log-rank p = 0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed. Interpretation: CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS. Funding: The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.

Gold Coast diagnostic criteria: Implications for ALS diagnosis and clinical trial enrollment.

Diagnostic criteria for amyotrophic lateral sclerosis (ALS) are complex, incorporating multiple levels of certainty from possible through to definite, and are thereby prone to error. Specifically, interrater variability was previously established to be poor, thereby limiting utility as diagnostic enrollment criteria for clinical trials. In addition, the different levels of diagnostic certainty do not necessarily reflect disease progression, adding confusion to the diagnostic algorithm. Realizing these inherent limitations, the World Federation of Neurology, the International Federation of Clinical Neurophysiology, the International Alliance of ALS/MND Associations, the ALS Association (United States), and the Motor Neuron Disease Association convened a consensus meeting (Gold Coast, Australia, 2019) to consider the development of simpler criteria that better reflect clinical practice, and that could merge diagnostic categories into a single entity. The diagnostic accuracy of the novel Gold Coast criteria was subsequently interrogated through a large cross-sectional study, which established an increased sensitivity for ALS diagnosis when compared with previous criteria. Diagnostic accuracy was maintained irrespective of disease duration, functional status, or site of disease onset. Importantly, the Gold Coast criteria differentiated atypical phenotypes, such as primary lateral sclerosis, from the more typical ALS phenotype. It is proposed that the Gold Coast criteria should be incorporated into routine practice and clinical trial settings.

Study protocol of RESCUE-ALS: A Phase 2, randomised, double-blind, placebo-controlled study in early symptomatic amyotrophic lateral sclerosis patients to assess bioenergetic catalysis with CNM-Au8 as a mechanism to slow disease progression.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive and universally fatal neurodegenerative disorder. In Europe, Australia and Canada, riluzole is the only approved therapeutic agent for the treatment of ALS, while in the USA, riluzole and edaravone have been approved by the Food and Drug Administration (FDA) . Neither riluzole nor edaravone treatment has resulted in substantial disease-modifying effects. There is, therefore, an urgent need for drugs that result in safe and effective treatment. Here, we present the design and rationale for the phase 2 RESCUE-ALS study, investigating the novel nanocatalytic drug, CNM-Au8, as a therapeutic intervention that enhances the metabolic and energetic capacity of motor neurones. CNM-Au8 is an aqueous suspension of clean-surfaced, faceted gold nanocrystals that have extraordinary catalytic capabilities, that enhance efficiencies of key metabolic reactions, while simultaneously reducing levels of reactive oxygen species. This trial utilises a novel design by employing motor unit number index (MUNIX), measured by electromyography, as a quantitative measure of lower motor neurone loss and as an early marker of ALS disease progression. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, parallel group, placebo-controlled study of the efficacy, safety, pharmacokinetics and pharmacodynamics of CNM-Au8 in ALS patients. Patients will be randomised 1:1 to either receive 30 mg of CNM-Au8 once daily or matching placebo over a 36-week double-blind treatment period. Efficacy will be assessed as the change in motor neurone loss as measured by electromyography (eg, MUNIX, the primary endpoint; and secondary endpoints including MScanFit, motor unit size index, Split Hand Index, Neurophysiology Index). Exploratory endpoints include standard clinical and quality of life assessments. ETHICS AND DISSEMINATION: RESCUE-ALS was approved by the Western Sydney Local Health District Human Research Ethics Committee (Ethics Ref: 2019/ETH12107). Results of the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04098406.

Nanocatalytic activity of clean-surfaced, faceted nanocrystalline gold enhances remyelination in animal models of multiple sclerosis.

Development of pharmacotherapies that promote remyelination is a high priority for multiple sclerosis (MS), due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. Furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of myelin differentiation markers. Additional in vitro data demonstrated that these gold nanocrystals act via a novel energy metabolism pathway involving the enhancement of key indicators of aerobic glycolysis. In response to gold nanocrystals, co-cultured central nervous system cells exhibited elevated levels of the redox coenzyme nicotine adenine dinucleotide (NAD+), elevated total intracellular ATP levels, and elevated extracellular lactate levels, along with upregulation of myelin-synthesis related genes, collectively resulting in functional myelin generation. Based on these preclinical studies, clean-surfaced, faceted gold nanocrystals represent a novel remyelinating therapeutic for multiple sclerosis.