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.

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study.

BACKGROUND: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. OBJECTIVE AND METHODS: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. RESULTS: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. CONCLUSION: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. TRIAL REGISTRATION: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18.

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.

Application of an evidence-based, out-patient treatment strategy for COVID-19: Multidisciplinary medical practice principles to prevent severe disease.

The COVID-19 pandemic has devastated individuals, families, and institutions throughout the world. Despite the breakneck speed of vaccine development, the human population remains at risk of further devastation. The decision to not become vaccinated, the protracted rollout of available vaccine, vaccine failure, mutational forms of the SARS virus, which may exhibit mounting resistance to our molecular strike at only one form of the viral family, and the rapid ability of the virus(es) to hitch a ride on our global transportation systems, means that we are will likely continue to confront an invisible, yet devastating foe. The enemy targets one of our human physiology's most important and vulnerable life-preserving body tissues, our broncho-alveolar gas exchange apparatus. Notwithstanding the fear and the fury of this microbe's potential to raise existential questions across the entire spectrum of human endeavor, the application of an early treatment intervention initiative may represent a crucial tool in our defensive strategy. This strategy is driven by evidence-based medical practice principles, those not likely to become antiquated, given the molecular diversity and mutational evolution of this very clever "world traveler".

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.

Prehistoric enemies within: The contribution of human endogenous retroviruses to neurological diseases. Meeting report: "Second International Workshop on Human Endogenous Retroviruses and Disease", Washington DC, March 13th and 14th 2017.

The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.

A placebo randomized controlled study to test the efficacy and safety of GNbAC1, a monoclonal antibody for the treatment of multiple sclerosis - Rationale and design.

BACKGROUND: GNbAC1, a humanized monoclonal antibody, is an innovative treatment currently in development for multiple sclerosis (MS) which, contrary to the immunomodulation/immunosuppressive mechanism of action of most of the MS drugs, targets specifically a protein of endogenous retroviral origin supposed to be critical in MS pathogenesis. METHODS: This trial is a randomized placebo controlled 4-arm study with the objective of demonstrating the efficacy of repeated doses of GNbAC1 on the cumulative number of T1 Gd-enhancing lesions measured from Week 12 to 24 in patients with relapsing remitting MS (RRMS). Two hundred sixty patients with RRMS are planned to be included. Three doses of GNbAC1 will be tested versus placebo: 6mg/kg, 12mg/kg and 18mg/kg, administered intravenously, with 4-week administration intervals. The design is based on the classic 24-week placebo-controlled repeated brain MRI trial design (Period 1), with an extension of 24 weeks during which placebo patients will be re-randomized to one of the three doses of GNbAC1 to assess efficacy and safety of prolonged treatment of GNbAC1 (Period 2). The primary endpoint is the cumulative number of new Gadolinium enhanced T1 lesions measured using repeated brain magnetic resonance imaging (MRI) scans from Week 12 to 24; secondary endpoints, including additional MRI and clinical endpoints, will be assessed at the end of both Periods 1 and 2. Pharmacokinetics and biomarkers will be assessed in serum in all patients at several time points and also in cerebrospinal fluid in a subgroup of patients. To alleviate potential ethical concerns regarding placebo administration in MS, an early escape from trial will be implemented for patients with a worsening clinical condition during trial. CONCLUSION: This dose-finding study should provide the first proof-of-concept of an innovative therapeutic approach for MS. The constraints of using a placebo group in RRMS patients while optimizing the trial power to evidence a new mechanism of action is discussed.

On being a neurologist in industry.

Neurologists in the pharmaceutical industry have an attractive and rewarding career path that offers the chance to participate in large projects, contribute directly to clinical breakthroughs in drug development, and translate biomarker research into applied practice. This article describes the different and common features of corporate compared to academic environments, and highlights the key factors necessary for success in the business world. Integrity, communication skills, an open-minded attitude, and an ability to handle stress and manage complex organizational structures are prerequisites that enable physician-neuroscientists to pursue successful and exciting careers in the corporate environment.

EDSS variability before randomization may limit treatment discovery in primary progressive MS.

BACKGROUND: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. METHODS: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. RESULTS: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. CONCLUSION: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.

Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.

BACKGROUND: B lymphocytes are implicated in the pathogenesis of multiple sclerosis. We aimed to assess efficacy and safety of two dose regimens of the humanised anti-CD20 monoclonal antibody ocrelizumab in patients with relapsing-remitting multiple sclerosis. METHODS: We did a multicentre, randomised, parallel, double-blind, placebo-controlled study involving 79 centres in 20 countries. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1:1) via an interactive voice response system to receive either placebo, low-dose (600 mg) or high-dose (2000 mg) ocrelizumab in two doses on days 1 and 15, or intramuscular interferon beta-1a (30 µg) once a week. The randomisation list was not disclosed to the study centres, monitors, project statisticians or to the project team at Roche. All groups were double blinded to group assignment, except the interferon beta-1a group who were rater masked. At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of gadolinium-enhancing lesions (GEL) and T1-weighted MRI at weeks 12, 16, 20, and 24. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00676715. FINDINGS: 218 (99%) of the 220 randomised patients received at least one dose of ocrelizumab, 204 (93%) completed 24 weeks of the study and 196 (89%) completed 48 weeks. In the intention-to-treat population of 218 patients, at week 24, the number of gadolinium-enhancing lesions was 89% (95% CI 68-97; p<0·0001) lower in the 600 mg ocrelizumab group than in the placebo group, and 96% (89-99; p<0·0001) lower in the 2000 mg group. In exploratory analyses, both 600 mg and 2000 mg ocrelizumab groups were better than interferon beta-1a for GEL reduction. We noted serious adverse events in two of 54 (4%; 95% CI 3·0-4·4) patients in the placebo group, one of 55 (2%; 1·3-2·3) in the 600 mg ocrelizumab group, three of 55 (5%; 4·6-6·3) in the 2000 mg group, and two of 54 (4%; 3·0-4·4) in the interferon beta-1a group. INTERPRETATION: The similarly pronounced effects of B-cell depletion with both ocrelizumab doses on MRI and relapse-related outcomes support a role for B-cells in disease pathogenesis and warrant further assessment in large, long-term trials. FUNDING: F Hoffmann-La Roche Ltd, Biogen Idec Inc.

The role of optical coherence tomography in multiple sclerosis: expert panel consensus.

Optic neuritis (ON), a common manifestation of multiple sclerosis (MS), often occurs as the initial manifestation of central nervous system demyelination or develops during the course of this disease. Since the retinal nerve fiber layer (RNFL) is composed only of unmyelinated axons, measuring RNFL thickness represents a viable method of monitoring axonal loss in these patients. Optical coherence tomography (OCT) is a noninvasive, noncontact, accurate, and reproducible technique that quantitates the thickness of the peripapillary RNFL, fovea, and macula. Because of its potential role in defining axonal loss in ON and in assessing longitudinal changes in the RNFL before and after MS treatment, a multidisciplinary expert panel was charged with the following tasks: assess the current capabilities of OCT; review the current data about OCT, ON, and MS; and determine whether OCT could be a primary or secondary outcome measure in future MS clinical trials. The panel concluded that: [1] OCT is valid and reproducible; [2] OCT has yielded some important limited data concerning cross-sectional studies with ON and MS; [3] more studies are required to correlate OCT results with other measures of MS disease activity; [4] after correlation with these other measures and upon agreement of standardized technical and statistical methods, OCT may evolve into a important primary or secondary outcome metric for MS clinical trials and patient care.

Use of gabapentin for postherpetic neuralgia: results of two randomized, placebo-controlled studies.

BACKGROUND: Postherpetic neuralgia (PHN), which affects up to 70% of elderly persons with herpes zoster, can have debilitating effects, including physical and social disability and significant psychological distress. A variety of agents have been used, either singly or in combination, to control PHN, including topical and oral analgesics, antidepressants, and antiepileptic drugs (AEDs). However, PHN often proves refractory to these therapies. OBJECTIVE: This article reviews available data on the use of the newer AED gabapentin for the control of PHN. METHODS: A MEDLINE search was undertaken to identify all randomized, placebo-controlled trials on the use of gabapentin in PHN. The search terms were gabapentin and postherpetic neuralgia. RESULTS: The literature search identified 2 published studies of the efficacy of gabapentin in a total of 563 patients with PHN that had persisted for at least 3 months after the healing of herpes zoster rash. The studies employed multiple outcome measures, including visual analog and Likert scales for pain intensity, and quality-of-life and functional measures that included the Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and the Profile of Mood States. At maximum target dosages of 1800 to 3600 mg/d, gabapentin produced significant reductions in mean daily pain scores compared with placebo on both visual analog(P < 0.001) and Likert scales (P < 0.01). Improvements were also seen on the SF-36 subscales for physical functioning, bodily pain, vitality, and mental health(P < 0.01). CONCLUSION: Gabapentin may provide benefits in terms of alleviation of pain and overall quality of life in patients with chronic PHN.

Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials.

BACKGROUND: Pain is one of the most common reasons for seeking medical attention, and neuropathic pain is among the most common types of pain. Despite its prevalence, neuropathic pain is often underrecognized and inadequately treated. Many cases are refractory to the medications traditionally used for pain, such as nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are considered first-line agents for neuropathic pain, but their use is limited by unwanted side effects and a risk of cardiovascular mortality. OBJECTIVES: The goals of this article were to review data on the efficacy and tolerability of gabapentin in the treatment of neuropathic pain in adults and to determine the optimal dosing schedule. METHODS: Randomized controlled studies of gabapentin for neuropathic pain were identified through a search of PubMed and MEDLINE from 1966 to the present using the search terms gabapentin, randomized, placebo, and pain. Abstracts of identified articles were screened for study size (>100 patients per treatment arm) and use of appropriate efficacy measures. A separate review based on information provided by the manufacturer of gabapentinaand clinical trial Web sites was conducted to ascertain whether there had been any other relevant industry- or government-sponsored trials. The manufacturer provided additional unpublshed study data. RESULTS: Data from 5 randomized, placebo-controlled trials were included in the review, 1 of which has not yet been published. Gabapentin was effective in the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. It relieved symptoms of allodynia, burning pain, shooting pain, and hyperesthesia. Adverse effects were typically mild to moderate and usually subsided within approximately 10 days from the initiation of treatment. Based on available data, it appears that treatment should be started at a dose of 900 mg/d (300 mg/d on day 1, 600 mg/d on day 2, and 900 mg/d on day 3). Additional titration to 1800 mg/d is recommended for greater efficacy. Doses up to 3600 mg/d may be needed in some patients. The effective dose should be individualized according to patient response and tolerability. CONCLUSION: At doses of 1800 to 3600 mg/d, gabapentin was effective and well tolerated in the treatment of adults with neuropathic pain.