Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic ...lateral sclerosis (ALS) are not known.
In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.
A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.
Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
Summary Background Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and ...calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. Methods In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov , number NCT00983983. Findings Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0·06; HC/HC vs control, p=0·06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0·0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none 0% of eight in the HC/HC group vs three 50% of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0·03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. Interpretation Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. Funding Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.
GGGGCC repeat expansion in C9ORF72, which can be translated in both sense and antisense directions into five dipeptide repeat (DPR) proteins, including poly(GP), poly(GR), and poly(GA), is the most ...common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we developed sensitive assays that can detect poly(GA) and poly(GR) in the cerebrospinal fluid (CSF) of patients with C9ORF72 mutations. CSF poly(GA) and poly(GR) levels did not correlate with age at disease onset, disease duration, or rate of decline of ALS Functional Rating Scale, and the average levels of these DPR proteins were similar in symptomatic and pre-symptomatic patients with C9ORF72 mutations. However, in a patient with C9ORF72-ALS who was treated with antisense oligonucleotide (ASO) targeting the aberrant C9ORF72 transcript, CSF poly(GA) and poly(GR) levels decreased approximately 50% within 6 weeks, indicating they may serve as sensitive fluid-based biomarkers in studies directed against the production of GGGGCC repeat RNAs or DPR proteins.
Introduction/Aims
We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients.
Methods
Twenty‐two participants, whose peripheral blood ...mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to three tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 wk in a double‐blind fashion for 16 wk and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358Ala polymorphism of the interleukin 6 receptor (IL‐6R) gene.
Results
Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C‐reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (−3.0‐fold relative change, P < .001). CSF CRP reduction (−1.8‐fold relative change, P = .01) was associated with IL‐6R C allele count. No differences in PBMC gene expression or clinical measures were observed between groups.
Discussion
Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL‐6R Asp358Ala genotype. IL‐6 trans‐signaling may mediate a distinct central nervous system response in individuals inheriting the IL‐6R C allele. These results warrant further study in ALS patients where IL‐6R genotype and CRP levels may be useful enrichment biomarkers.
Objectives
To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase‐like vesicle‐associated (CAMKV).
Methods
...Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain‐based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top‐ranking candidate antigen. Western blots, confocal microscopy, immune‐absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV‐specific assays (cell‐based fixed and live and Western blot) provided additional confirmation.
Results
Of 5 CAMKV‐IgG positive patients, 3 were women (median symptom‐onset age was 59 years; range, 53–74). Encephalitis‐onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities all patients, caudate head T2 hyperintensities 3, and cortical diffusion weighted hyperintensities 2). None had post‐gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine‐differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non‐Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab 1, pembrolizumab 1). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids 4, IVIG 2), though 3 died from cancer.
Interpretation
CAMKV‐IgG is a biomarker of immunotherapy‐responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21–33
Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human ...GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.
NEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week qow) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.
Twenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of -0.473 per year (-1.188 to 0.242) and -0.648 per year (-1.061 to -0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of -0.701 per year (-1.571 to 0.169) and -0.846 per year (-1.567 to -0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged <45 years at NEO1 enrollment in both the Naive and Switch Groups.
Avalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.
This study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.
NCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1-August 19, 2013; NEO-EXT-February 27, 2014.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Though many molecular and genetic causes are thought to serve as ...predisposing or disease propagating factors, the underlying pathogenesis of the disease is not known. Recent discoveries have demonstrated the presence of inflammation propagating substrates in the central nervous system of patients afflicted with ALS. Over the past decade, this hypothesis has incited an effort to better understand the role of the immune system in ALS and has led to the trial of several potential immune-modulating therapies. Here, we briefly review advances in the role of such therapies. The clinical trials discussed here are currently ongoing or have been concluded at the time of writing.
Objective
To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their ...utility as pharmacodynamic biomarkers for monitoring treatment effects.
Methods
De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations.
Results
We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups.
Interpretation
Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials.
ABSTRACT
Introduction: A subset of regulatory B cells in humans and mice has been defined functionally by their ability to produce interleukin (IL)‐10. We characterized IL‐10‐producing B (B10) cells ...in myasthenia gravis (MG) patients and correlated them with disease activity and responsiveness to rituximab therapy. Methods: Frequencies of B10 cells from MG patients and healthy controls were monitored by fluorescence‐activated cell sorting (FACS). Results: MG patients had fewer B10 cells than controls, which was associated with more severe disease status. Moreover, patients who responded well to rituximab therapy exhibited rapid repopulation of B10 cells, whereas in patients who did not respond well to rituximab, B10 cell repopulation was delayed. The kinetics of B10 cells were related to the responsiveness to rituximab in MG. Conclusions: We have characterized a specific subset of B10 cells in MG patients which may serve as a marker for disease activity and responsiveness to immune therapy. Muscle Nerve 49:487–494, 2014
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