Trial Summary
What is the purpose of this trial?This is a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase II study to evaluate the efficacy and safety of VHB937 in participants with early-stage ALS (within 2 years of ALS symptoms onset). The study comprises a core double-blind (DB) 40-week treatment period followed by an open label extension (OLE).
Is the drug VHB937 a promising treatment for ALS?
VHB937, also known as VHB837, shows promise as a treatment for ALS because research suggests that increasing levels of a related protein, VAPB, can slow down the progression of the disease in animal models. This could mean that VHB937 might help protect nerve and muscle health in ALS patients.
45678What safety data exists for VHB937 or VHB837 in ALS treatment?
The provided research does not contain specific safety data for VHB937 or VHB837 in ALS treatment. The studies mentioned focus on other treatments like sodium phenylbutyrate-taurursodiol, edaravone, and EphA4 targeting agents. No safety data for VHB937 or VHB837 is available in the given research.
311121314What data supports the idea that VHB937 for ALS is an effective drug?
The available research does not provide specific data supporting the effectiveness of VHB937 for ALS. Instead, it highlights the effectiveness of another drug, sodium phenylbutyrate-taurursodiol (PB-TURSO), which was shown to be safe and effective in a trial and has been approved in Canada and the USA. This suggests that while there are promising treatments for ALS, there is no direct evidence from the provided information that VHB937 is effective for ALS.
1291014Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot use other investigational drugs or any prohibited medications. If you are on a stable dose of an approved ALS treatment, you may continue with it.
Eligibility Criteria
This trial is for adults over 18 with early-stage ALS, diagnosed within the last two years and having mild symptoms. Participants must not have started any ALS treatment or be on a stable approved dose. They should also have a certain level of breathing function and agree to use strict contraception if they can have children.Inclusion Criteria
My ALS diagnosis has been confirmed by the trial's doctors.
I am 18 years old or older.
My ALS symptoms are mild, with an ALSFRS-R score of 30 or more.
I can exhale at least 60% of the expected air volume for my age, sex, and height.
Participant Groups
The study tests VHB937 against a placebo in people with early-stage ALS. It's randomized (participants are put into groups by chance), double-blind (neither doctors nor participants know who gets what), and includes an initial 40-week treatment period followed by an open label phase where everyone knows what they're getting.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Arm 1Experimental Treatment1 Intervention
I.V. infusions every 4 weeks
Group II: Arm 2Placebo Group1 Intervention
I.V. infusions every 4 weeks
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Nerve and Muscle Center of TexasHouston, TX
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Who is running the clinical trial?
Novartis PharmaceuticalsLead Sponsor
References
Early symptom progression rate is related to ALS outcome: a prospective population-based study. [2019]To define the factors related to ALS outcome in a population-based, prospective survey.
[The changes of clinical characteristics in 100 Japanese amyotrophic lateral sclerosis patients between 1980 and 2000]. [2006]To define changes of clinical features in amyotrophic lateral sclerosis (ALS) over the past 20 years and prognostic indicators of ALS from a single hospital-based retrospective survey.
An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system. [2019]We detected disproportionate reporting of amyotrophic lateral sclerosis (ALS) with HMG-CoA-reductase inhibitors (statins) in the Food and Drug Administration's (FDA) spontaneous adverse event (AE) reporting system (AERS).
VAPB and C9orf72 mutations in 1 familial amyotrophic lateral sclerosis patient. [2017]Previously, we have reported amyotrophic lateral sclerosis (ALS) families with multiple mutations in major ALS-associated genes. These findings provided evidence for an oligogenic basis of ALS. In our present study, we screened a cohort of 755 sporadic ALS patients, 111 familial ALS patients (97 families), and 765 control subjects of Dutch descent for mutations in vesicle-associated membrane protein B (VAPB). We have identified 1 novel VAPB mutation (p.V234I) in a familial ALS patient known to have a chromosome 9 open reading frame 72 (C9orf72) repeat expansion. This p.V234I mutation was absent in control subjects, located in a region with high evolutionary conservation, and predicted to have damaging effects. Taken together, these findings provide additional evidence for an oligogenic basis of ALS.
No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland. [2015]Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p.Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p.Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p.Asp130Glu VAPB mutation is unrelated to the disease process. In conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.
Expression of vesicle-associated membrane-protein-associated protein B cleavage products in peripheral blood leukocytes and cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. [2015]Vesicle-associated membrane-protein-associated protein B (VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER function, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminal domain, named MSP, is cleaved and secreted, serving as an extracellular ligand. VAPB mutations are linked to autosomal-dominant motor neuron diseases, including amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is also suspected in sporadic ALS (SALS).
Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. [2015]Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014.
Neuronal overexpression of human VAPB slows motor impairment and neuromuscular denervation in a mouse model of ALS. [2018]Four mutations in the VAMP/synaptobrevin-associated protein B (VAPB) gene have been linked to amyotrophic lateral sclerosis (ALS) type 8. The mechanism by which VAPB mutations cause motor neuron disease is unclear, but studies of the most common P56S variant suggest both loss of function and dominant-negative sequestration of wild-type protein. Diminished levels of VAPB and its proteolytic cleavage fragment have also been reported in sporadic ALS cases, suggesting that VAPB loss of function may be a common mechanism of disease. Here, we tested whether neuronal overexpression of wild-type human VAPB would attenuate disease in a mouse model of familial ALS1. We used neonatal intraventricular viral injections to express VAPB or YFP throughout the brain and spinal cord of superoxide dismutase (SOD1) G93A transgenic mice. Lifelong elevation of neuronal VAPB slowed the decline of neurological impairment, delayed denervation of hindlimb muscles, and prolonged survival of spinal motor neurons. Collectively, these changes produced a slight but significant extension in lifespan, even in this highly aggressive model of disease. Our findings lend support for a protective role of VAPB in neuromuscular health.
Introduction to supplement: the current status of treatment for ALS. [2018]ALS is a lethal neurodegenerative disease wherein the diagnosis is often delayed. Our understanding of the pathobiology is slowly expanding, and the number of new genes is rapidly increasing. The development of potential treatments targeting specific mechanisms is beginning to offer hope. Evidence-based treatments and the development of quality measures have raised the standard of care. The current status of treatment for ALS includes one drug riluzole that slows progression modestly, and another drug edaravone that was recently approved by FDA to slow ALS progression. Multidisciplinary clinics and symptomatic treatments ease the burden of ALS and prolong life. An overview of these treatments is provided here.
Development and Validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). [2021]A new outcome measure for overall disability level with improved responsiveness is needed for amyotrophic lateral sclerosis (ALS) clinical trials.
Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System. [2021]Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed.
Analysis of the US Safety Data for Edaravone (Radicava®) From the Third Year After Launch. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US.
EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes. [2022]Amyotrophic lateral sclerosis (ALS) is a degenerative disease that progressively destroys motor neurons (MNs). Earlier studies identified EphA4, a receptor tyrosine kinase, as a possible disease-modifying gene. The complex interplay between the EphA4 receptor and its ephrin ligands in motor neurons and astrocytes has not yet been fully elucidated and includes a putative pro-apoptotic activity of the unbound receptor compared to ephrin-bound receptor. We recently reported that astrocytes from patients with ALS induce cell death in co-cultured MNs. Here we found that first-generation synthetic EphA4 agonistic agent 123C4, effectively protected MNs when co-cultured with reactive astrocytes from patients with ALS from multiple subgroups (sALS and mutant SOD1). Newer generation and more potent EphA4 agonistic agents 150D4, 150E8, and 150E7 provided effective protection at a lower therapeutic dose. Combined, the data suggest that the development of EphA4 agonistic agents provides potentially a promising therapeutic strategy for patients with ALS.
An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis. [2023]Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved disease-modifying therapies prior to 2022. The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in persons with ALS (PALS), leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022.