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The New England Journal of Medicine Sep 2020Sodium 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... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.).
Topics: Aged; Amyotrophic Lateral Sclerosis; Disease Progression; Double-Blind Method; Drug Combinations; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Phenylbutyrates; Severity of Illness Index; Taurochenodeoxycholic Acid; Treatment Outcome
PubMed: 32877582
DOI: 10.1056/NEJMoa1916945 -
Cells May 2023Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.
Topics: Humans; Amyotrophic Lateral Sclerosis; Riluzole; Motor Neurons; Biomarkers; Disease Progression
PubMed: 37296644
DOI: 10.3390/cells12111523 -
Nature Reviews. Nephrology Aug 2020Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common... (Review)
Review
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
Topics: Arginine; Carnitine; Child; Child, Preschool; Continuous Renal Replacement Therapy; Delphi Technique; Diet, Protein-Restricted; Humans; Hybrid Renal Replacement Therapy; Hyperammonemia; Infant; Infant, Newborn; Parenteral Nutrition; Peritoneal Dialysis; Phenylacetates; Phenylbutyrates; Practice Guidelines as Topic; Renal Dialysis; Sodium Benzoate; Urea Cycle Disorders, Inborn; Vitamin B Complex
PubMed: 32269302
DOI: 10.1038/s41581-020-0267-8 -
Biomedicine & Pharmacotherapy =... Apr 2023Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with high mortality and morbidity rate affecting both upper and lower motor neurons (MN). Muscle force reduction, behavioral change, pseudobulbar affect, and cognitive impairments are the most common clinical manifestations of ALS. The main physiopathology of ALS is still unclear, though several studies have identified that oxidative stress, proteinopathies, glutamate-related excitotoxicity, microglial activation, and neuroinflammation may be involved in the pathogenesis of ALS. From 1995 until October 2022, only Riluzole, Dextromethorphan Hydrobromide (DH) with Quinidine sulfate (Q), Edaravone, and Sodium phenylbutyrate with Taurursodiol (PB/TUDCO) have achieved FDA approval for ALS treatment. Despite the use of these four approved agents, the survival rate and quality of life of ALS patients are still low. Thus, finding novel treatments for ALS patients is an urgent requirement. Masitinib, a tyrosine kinase inhibitor, emphasizes the neuro-inflammatory activity of ALS by targeting macrophages, mast cells, and microglia cells. Masitinib downregulates the proinflammatory cytokines, indirectly reduces inflammation, and induces neuroprotection. Also, it was effective in phase 2/3 and 3 clinical trials (CTs) by increasing overall survival and delaying motor, bulbar, and respiratory function deterioration. This review describes the pathophysiology of ALS, focusing on Masitinib's mechanism of action and explaining why Masitinib could be a promising actor in the treatment of ALS patients. In addition, Masitinib CTs and other competitor drugs in phase 3 CTs have been discussed.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Quality of Life; Seasons
PubMed: 36774721
DOI: 10.1016/j.biopha.2023.114378 -
Muscle & Nerve Aug 2022Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION/AIMS
Trials incorporating placebo-to-active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank-preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo-controlled and open-label extension (OLE) phases.
METHODS
Intent-to-treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed.
RESULTS
Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35-0.92) on ITT analysis and 0.39 (0.17-0.88) in the primary on-treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM-adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO-randomized subgroup who continued into the OLE phase versus the placebo-randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results.
DISCUSSION
Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.
Topics: Amyotrophic Lateral Sclerosis; Cross-Over Studies; Double-Blind Method; Humans; Survival Analysis
PubMed: 35508892
DOI: 10.1002/mus.27569 -
Muscle & Nerve Jan 2021An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized,... (Randomized Controlled Trial)
Randomized Controlled Trial
An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo. Participants completing the 6-month (24-week) randomized phase were eligible to receive PB-TURSO in the open-label extension. An all-cause mortality analysis (35-month maximum follow-up post-randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow-up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB-TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34-0.92; P = .023). Initiation of PB-TURSO treatment at baseline resulted in a 6.5-month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB-TURSO has both functional and survival benefits in ALS.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Phenylbutyrates; Taurochenodeoxycholic Acid; Time; Young Adult
PubMed: 33063909
DOI: 10.1002/mus.27091 -
Annals of Indian Academy of Neurology 2023Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of anterior horn cells with a dismal prognosis. Over a century since its description, we still do not have a cure for this disorder. Edaravone, Riluzole, and combination of phenylbutyrate and taurursodiol are a handful of FDA-approved drugs that only delay the progression of the disease by a few months. Tofersen, an antisense oligonucleotide, in SOD1 related ALS, has joined the bandwagon of FDA-approved drugs for ALS recently. It is a gene therapy that has been found to lower SOD1 concentrations and neurofilament light chain concentrations in blood and CSF, a known biomarker of ALS, leading to the accelerated approval of the drug. Although it did not show any statistically significant clinical improvement. In this article, we discuss the development and approval process of the first gene-based therapy, Tofersen, for ALS.
PubMed: 38022476
DOI: 10.4103/aian.aian_734_23