INTRODUCTION — Amyotrophic lateral sclerosis (ALS), first described by Charcot in the 19th century , is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death, with a median survival of three to five years.
The hallmark of ALS is the combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. The LMN findings of weakness, atrophy, and fasciculations are a direct consequence of muscle denervation. The UMN findings of hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord .
The existing and experimental disease-modifying pharmacologic treatment of ALS will be reviewed here. Other aspects of ALS are discussed separately.
●(See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis".)
●(See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
●(See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
●(See "Symptom-based management of amyotrophic lateral sclerosis".)
RILUZOLE — For all patients living with ALS, we recommend treatment with riluzole. Three separate mechanisms of riluzole are thought to reduce glutamate-induced excitotoxicity: inhibition of glutamic acid release, noncompetitive block of N-methyl-D-aspartate (NMDA) receptor-mediated responses, and direct action on the voltage-dependent sodium channel . However, its precise mechanism of action in ALS is unclear .
For all patients living with ALS, we recommend treatment with riluzole. Riluzole has been shown to prolong survival and slow functional deterioration in patients with ALS . Riluzole was approved for use by the United States Food and Drug Administration (FDA) in 1995 .
Efficacy — Patients most likely to benefit from riluzole therapy are those with definite or probable ALS with symptoms present for less than five years, a forced vital capacity (FVC) >60 percent of predicted, and no tracheostomy. However, all patients may benefit. The evidence that riluzole is beneficial comes from two multicenter randomized trials [6,7]:
●In a prospective, double-blind, placebo-controlled trial in 155 outpatients with ALS, survival at 12 months was significantly higher for patients receiving riluzole (100 mg/day) compared with controls (74 versus 58 percent) . For the subset of patients with bulbar-onset ALS, an even greater advantage for survival at 12 months emerged for the riluzole group (73 versus 35 percent).
●In a larger follow-up trial, 959 patients with clinically probable or definite ALS of less than five years' duration were randomly assigned treatment with riluzole (50 mg, 100 mg, or 200 mg daily) or placebo . After a median follow-up of 18 months, the primary outcome of survival without tracheostomy was significantly higher for the riluzole-treated group (100 mg/day) compared with controls (57 versus 50 percent; adjusted relative risk 0.65, 95% CI 0.50-0.85). Functional measures did not differ significantly among the groups.
Observational studies performed subsequent to the two riluzole randomized trials have largely corroborated a survival benefit of riluzole in more heterogenous clinical settings, independent of other factors [8,9]. While one retrospective analysis of individual patient-level data from the original trial suggested that the effect of riluzole was primarily to extend the time in stage 4 of the disease (as inferred by vital capacity ≤75 percent of predicted or gastrostomy tube insertion) , this effect has not been confirmed prospectively, and multiple other studies have found the benefit of riluzole to be equal or greater in "real-world" clinical practice compared with what was observed in the trials [8,9].
Guidelines — A 2009 American Academy of Neurology (AAN) practice parameter concluded that riluzole is safe and effective for slowing ALS progression to a modest degree . The AAN recommended that riluzole should be offered to slow disease progression in patients with ALS.
Patients for whom no randomized data support the use of riluzole but expert opinion suggests potential benefit include those who have :
●Suspected or possible ALS by El Escorial criteria
●Symptoms present for more than five years
●Vital capacity less than 60 percent of predicted
●Tracheostomy for prevention of aspiration only (ventilator independent)
Expert consensus suggests riluzole is of uncertain benefit in patients who have the following conditions:
●Tracheostomy required for ventilation
●Other incurable disorders
●Other forms of anterior horn cell disease
Dosing and adverse effects — The recommended dose of riluzole is 50 mg twice daily. It is well absorbed orally, with a bioavailability of 60 percent and an elimination half-life of 12 hours. Available preparations include tablet, suspension, and an orally disintegrating film. Metabolism is through the cytochrome P450 enzyme 1A2 (CYP1A2). The pharmacologic effects of riluzole may be affected by inhibitors of CYP1A2, such as theophylline and caffeine, which potentially may decrease the rate of riluzole elimination.
Riluzole is well tolerated, with the most significant adverse effects being gastrointestinal and hepatic. Neutropenia is extremely rare . The most common adverse effects of riluzole are asthenia, dizziness, gastrointestinal disorders, and elevations in liver enzyme activities.
Elevation of the liver transaminases can be expected with riluzole treatment . At least one alanine aminotransferase (ALT) level above the upper limit of normal (ULN) will occur in approximately one half of patients treated with riluzole, while elevations greater than three or five times the ULN are seen in 8 and 2 percent of patients, respectively . Liver function tests are indicated monthly for the first three months of riluzole treatment and every three months thereafter.
EDARAVONE — Edaravone slows functional deterioration in patients with ALS. Edaravone is a free-radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of ALS. While the evidence for the benefit of edaravone is clearest in patients with early ALS, as defined in the pivotal trial [16,17], there is no reason to believe that the population evaluated in that trial is biologically distinct from the greater ALS population.
We suggest edaravone for all patients with ALS. Edaravone was approved in intravenous (IV) formulation in 2015 and in oral formulation in 2022 for the treatment of ALS in Japan and Korea and received United States Food and Drug Administration (FDA) approval for all people with ALS in May 2017 .
Efficacy — The evidence of efficacy is derived largely from results of randomized controlled trials:
●An initial 24-week trial randomized 206 subjects with ALS who had a disease duration of three years, lived independently, and had forced vital capacity (FVC) of ≥70 percent . The primary outcome measure was the change in the revised ALS functional rating scale (ALSFRS-R) score, in which higher scores indicate better function. After the 24-week treatment period, there was no statistically significant benefit for function on the ALSFRS-R score with edaravone treatment compared with placebo (-5.7 versus -6.35; mean difference 0.65, 95% CI -0.90 to 2.19). However, a post hoc analysis showed a greater treatment effect in the subgroup of subjects with definite or probable ALS at entry who had scores of 2 or more on all items of the ALSFRS-R, an FVC of at least 80 percent at baseline, and a disease duration of two years or less [16,19].
●A subsequent controlled trial enrolled 137 Japanese participants with early-stage ALS who were selected to match the subset of participants defined by the post hoc analysis of the previous trial (ie, definite or probable ALS by the El Escorial criteria, a disease duration of two years or less, independent living status, scores of 2 or more on all items of ALSFRS-R, and an FVC of ≥80 percent) . Participants were randomly assigned to treatment with edaravone or placebo. At 24 weeks, there was a smaller decline in function, measured by the ALSFRS-R, for the edaravone group compared with the placebo group (-5.01 versus -7.50; difference 2.49, 95% CI 0.99-3.98). This change was considered clinically significant, with a slowing of approximately 33 percent [16,20]. In addition, participants assigned to edaravone experienced less decline on the ALS Assessment Questionnaire (ALSAQ-40). Open-label follow-up showed continued benefit out to 48 weeks .
Dosing and adverse effects — Edaravone is given either as a 60 mg intravenous infusion over 60 minutes or as a 105 mg (5 mL) oral suspension to be taken in the morning after overnight fasting [22,23]. Dosing schedules for intravenous and oral edaravone are the same: treatment is started with daily dosing for 14 days, followed by 14 days off treatment. Subsequent treatment cycles involve daily edaravone 10 days within a 14-day period, followed by 14 days off treatment. Other oral dosing regimens and similar compounds are being evaluated [24,25]
The most frequent adverse reactions among subjects treated with edaravone in clinical studies were injection-site contusion, gait disturbance, and headache . Edaravone contains sodium bisulfite, which may cause allergic reactions including asthmatic episodes in susceptible individuals . Sulfites can cause potentially serious asthmatic reactions in as many as 5 percent of patients with asthma, whereas individuals without asthma are rarely affected. (See "Allergic and asthmatic reactions to food additives", section on 'Sulfites and related compounds'.)
SODIUM PHENYLBUTYRATE-TAURURSODIOL — Sodium phenylbutyrate is a histone deacetylase inhibitor that reduces an adaptive stress response in the endoplasmic reticulum. Taurursodiol (also known as ursodoxicoltaurine) appears to increase the threshold of cellular apoptosis by maintaining mitochondrial integrity through reduced membrane permeability. A coformulation of both agents, sodium phenylbutyrate-taurursodiol (PB-TURSO), is used to reduce neuronal cell death.
We suggest PB-TURSO for all patients with ALS. PB-TURSO has been shown to slow clinical deterioration in patients with ALS. It was conditionally approved for use in Canada in June 2022 and approved by the United States Food and Drug Administration (FDA) for all patients with ALS in September 2022 [26,27].
Efficacy — PB-TURSO was assessed in a placebo-controlled trial of 137 patients with ALS who were within 18 months of symptom onset . More than 75 percent of patients were also taking riluzole or edaravone (28 percent were taking both) and the median revised ALS functional rating scale (ALSFRS-R) score was 36 (maximum score is 48). By 24-week follow-up, those treated with PB-TURSO showed a slower rate of decline on the ALSFRS-R than those treated with placebo (-1.24 versus -1.66; 0.42 point per month difference, 95% CI 0.03-0.81). During the 24-week randomized, double blind period, there was no change in levels of neurofilament serum biomarkers or time to death associated with treatment but a trend toward slower decline in vital capacity and muscle strength with treatment. In a subsequent analysis of patients who continued open-label treatment (up to 35 months), those originally randomized to PB-TURSO had a longer median time to tracheostomy/permanent assisted ventilation by 7.3 months (HR 0.51, 95% CI 0.32-0.84) and longer median time to first hospitalization (HR 0.56, 95% CI 0.34-0.95) .
A large confirmatory trial further assessing the efficacy and safety of PB-TURSO for 48 weeks is underway in the United States and Europe .
Dosing and adverse effects — PB-TURSO is a powder (containing 3 g sodium phenylbutyrate and 1 g taurursodiol) to be administered as a suspension dissolved in 250 milliliters of water and taken orally (or by gastric tube) once daily for three weeks, then twice daily thereafter [27,31]. Most common adverse effects with PB-TURSO include diarrhea, abdominal pain, nausea, and upper respiratory tract infection. PB-TURSO may cause fluid retention and should be used with caution in patients sensitive to salt intake, including those with hypertension, kidney disease, and heart failure. PB-TURSO may affect concentration of medications that are substrates of several cytochrome P450 (CYP) enzymes, inhibiting CYP2C8 and CYP2B6 and inducing CYP1A2, CYP2B6, and CYP3A4 isoenzymes.
Initial use of the medication may be limited by availability and high cost.
Novel agents — A wide range of agents targeting different aspects of the pathophysiology of ALS are being explored in both sporadic and familial ALS [32-36]:
●Antisense oligonucleotide therapy for genetic forms of ALS
•Gene-silencing therapy uses antisense oligonucleotides to downregulate or silence pathologic variant genes for genetic forms of ALS. The antisense strategy targets specific RNA sequences by constructing complementary oligonucleotides that bind to the native mRNA sequences and reduce their translation and subsequent protein expression.
•Intraventricular infusion of antisense oligonucleotides to SOD1 reduces both SOD1 protein and mRNA levels and slows disease progression in studies using rat models . In a dose-escalating human trial, the antisense oligonucleotide tofersen given intrathecally over 12 weeks to 50 patients with ALS due to SOD1 variant showed reduction in cerebrospinal fluid SOD1 concentrations . In a subsequent phase III study, 108 patients with ALS were assigned to intrathecal tofersen 100 mg or placebo in a 2:1 ratio . The primary outcome of change in baseline revised ALS functional rating scale (ALSFRS-R) by 28 weeks was similar for tofersen and placebo. However, several trends favoring tofersen were reported in secondary and exploratory endpoints, including a reduction in SOD1 protein and neurofilaments and slower decline in motor and respiratory function. Patients who received at least 6 months of tofersen also showed slowing of progression on multiple measures, whether initially randomized to placebo or active treatment. Patients in this study continue to be actively followed to assess for longer term benefits. The United States Food and Drug Association (FDA) has accepted the New Drug Application (NDA) for review.
●Healey Platform Trial (zilucoplan, verdiperstat, CNM-Au8, pridopidine, SLS-005 trehalose) – The Healey ALS Platform Trial is a multicenter, multiregimen clinical trial evaluating the safety and efficacy of multiple investigational products tested simultaneously and sequentially, in a perpetual platform trial design dictated by a single master protocol. Each investigational product is tested in a regimen that is placebo matched. Participants will have an equal chance to be randomized to all regimens that are active at the time of screening. Once randomized to a regimen, participants will be randomized in a 3:1 ratio to study drug or placebo. Regimens under investigation in this trial are regimen A (zilucoplan), regimen B (verdiperstat), regimen C (CNM-Au8), regimen D (pridopidine), regimen E (SLS-005 trehalose). Regimen A was stopped early for futility and Regimen B was recently reported as negative. New regimens will be continuously added as new investigational products become available. The HEALEY ALS Platform Trial began enrollment in July 2020 .
●Skeletal muscle activators (eg, levosimendan [40,41], reldesemtiv ) – Levosimendan selectively binds to troponin C and is a calcium sensitizer to cardiac and skeletal muscles; the intravenous formulation has been indicated for acute worsening of severe heart failure. As a skeletal muscle activator, its use has been under investigation for its potential impact on respiratory muscles in ALS. In a phase II study, 66 ALS patients were randomized to oral levosimendan 1 mg daily, 1 mg two times a day, or placebo during three 14-day crossover periods . While the primary endpoint of sitting slow vital capacity (SVC) was similar between treatment and placebo, supine SVC favored levosimendan over placebo in a dose-dependent fashion, in a post hoc analysis. However, another phase III study of oral levosimendan did not meet the primary endpoint of a significant change from baseline in supine SVC at 12 weeks .
Reldesemtiv, a fast skeletal muscle troponin activator with limited penetration of the blood-brain barrier, was evaluated in a phase II, dose-ranging study in 458 ALS patients . The change in percent predicted of SVC at 12 weeks was similar between reldesemtiv and placebo as were secondary measures of changes in ALSFRS-R and muscle strength. Post hoc analyses pooling all active reldesemtiv-treated patients showed trends favoring reldesemtiv toward benefit in SVC, ALSFRS-R, and muscle strength . A phase III study to further evaluate these findings using reldesemtiv 300 mg twice daily is ongoing .
●Masitinib – Masitinib is a selective oral tyrosine kinase inhibitor, targeting mast cells and microglia cells known to have a prominent role in neuroinflammatory processes. The development of masitinib in ALS is postulated to exert neuroprotection by slowing microglial-related disease progression, reducing neuroinflammation, and modulating the neuronal microenvironment in both central and peripheral nervous systems. A double-blind study of 394 ALS patients randomly assigned (1:1:1) to receive riluzole (100 mg/day) plus placebo or masitinib at 4.5 or 3 mg/kg/day was completed. Followed by a blinded transition from phase II to phase II/III, a prospectively defined two-tiered design based on ALSFRS-R progression rate from disease onset to baseline was implemented. In the study, masitinib showed benefit over placebo with an ALSFRS-R progression rate between-group difference of 3.4 (95% CI 0.65-6.13) that corresponded to a 27 percent slowing in rate of functional decline . A confirmatory phase III study is ongoing .
●Neurotrophic factor (NTF)-secreting mesenchymal stromal cells (MSC-NTF cells) and other stem cell treatments [48-53] – A phase II study of 48 ALS patients randomized 3:1 participants to one dose of MSC-NTF cells or placebo and then followed for six months showed the study met its primary endpoint of safety. While the rate of disease progression in the overall study population was similar for treated and placebo participants, the rate of disease progression (ALSFRS-R slope) had improved at early time points . This study led to a larger phase III study to evaluate the safety and efficacy of repeated administrations of MSC in a predefined ALS subgroup of rapid progressors . The change in disease progression post-treatment was similar for the MSC-NTF treated group and placebo participants. However, changes were noted in cerebrospinal biomarkers of neuroinflammation, neurodegeneration, and neurotrophic factor support in MSC-NTF treated group, with no change in the placebo group .
Off-label use of other medications — Some medications used for other indications have been evaluated for benefit in ALS. There are several challenges that impact the ability of trials to detect an important clinical signal in ALS, including disease and patient heterogeneity. In some cases, previously studied drugs may need to be reexamined in a more selected patient group. Genetic variability in particular is increasingly understood and plays an important role in therapeutic development and trial design. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Genetic susceptibility in sporadic ALS' and "Familial amyotrophic lateral sclerosis".)
●Methylcobalamin – In vivo studies with ultrahigh-dose methylcobalamin injections in a mouse model of ALS have shown delayed progression of motor symptoms and neuropathologic changes . A phase II/III study of 373 patients with ALS in Japan reported that ultrahigh-dose methylcobalamin (25 or 50 mg intramuscular injections twice per week) was safe and well tolerated and with a trend toward clinical benefit . A subsequent phase III study found that patients with early-stage ALS who received methylcobalamin 50 mg intramuscular injections twice weekly for 16 weeks had slower functional decline than those who received placebo (mean decline in the ALSFRS-R score -2.66 versus -4.63; 95% CI 0.44-3.50) . These results suggest beneficial effects of treatment with ultrahigh-dose methylcobalamin in ALS, especially early on in the disease course.
●Lithium – A retrospective analysis of clinical and genetic data from the three randomized trials of lithium in ALS suggested that a signal of efficacy may have been missed in a small subset of patients who were homozygous for the C allele of a single nucleotide polymorphism (SNP) in the UNC13A gene . While this finding requires prospective confirmation, it underscores the importance of genetic data in trial design and analysis going forward.
●Vitamin E – Oxidative stress has been implicated in the pathogenesis of ALS due to the production of oxygen free radicals resulting in lipid peroxidation, cytoskeletal disruption, and damage to the mitochondria. As discussed earlier, there is evidence from randomized controlled trials that the antioxidant edaravone slows progression of ALS in some patients (see 'Edaravone' above). Randomized controlled trials have not shown benefit for other antioxidants. At least two trials have failed to demonstrate significant benefit of vitamin E as add-on therapy to riluzole in ALS. In the earlier study, subjects were randomly assigned to vitamin E 500 mg twice daily or placebo; there was no significant difference in disease progression at 12 months . In a subsequent 18-month trial, subjects were randomly assigned to either megadose vitamin E at 5000 mg/day or placebo . No significant difference was found between the rates of survival of the two groups. No significant adverse events were noted with doses as high as 5000 mg per day.
●N-acetylcysteine – In a randomized controlled trial testing the free-radical scavenger N-acetylcysteine (NAC), there was no significant difference in delay of progression of the disease between the treatment and placebo groups . However, there was a beneficial trend in survival for the patients with limb-onset disease.
Although some of these experimental therapeutics for ALS are available as prescription medications for other approved indications or as over-the-counter medications, the off-label use of these drugs for the treatment of ALS is strongly discouraged. These drugs should be used to treat ALS only in the context of a clinical trial or under the discretion of an experienced clinician.
A frequently updated list of drug trials can be found online from the ALS Association, the Northeast ALS Consortium, and ClinicalTrials.gov.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Motor neuron disease".)
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Amyotrophic lateral sclerosis (ALS)".)
SUMMARY AND RECOMMENDATIONS
●Established disease-modifying therapies – Clinical trials have demonstrated that disease-modifying treatments for ALS slow disease progression, increase the time to the need for tracheostomy or permanent assisted ventilation, and/or prolong survival. While clinical benefit for each of these agents was identified mostly in patients with early disease, all patients with ALS may benefit. (See 'Riluzole' above and 'Edaravone' above and 'Sodium phenylbutyrate-taurursodiol' above.)
•Initial treatment with riluzole – For all patients with ALS, we recommend initial treatment with riluzole (Grade 1A). Riluzole has been shown to prolong survival and slow disease progression in multiple clinical trials. Administration is by tablet, suspension, or an orally disintegrating film each at a dose of 50 mg twice daily. (See 'Riluzole' above.)
•Further treatment options – We also suggest treatment with edaravone and PB-TURSO for patients with ALS who are established on riluzole and those who are unwilling or unable to take riluzole (Grade 2B). Each of these options has shown benefit to slow disease progression. We typically begin each additional treatment option within weeks after starting the prior agent. (See 'Edaravone' above and 'Sodium phenylbutyrate-taurursodiol' above.)
-Edaravone is given by intravenous infusion or oral suspension once daily. Initial dosing is 14 days on treatment followed by 14 days off treatment, then maintenance dosing of 10 days within a 14-day interval on treatment followed by 14 days off.
-PB-TURSO is given as a coformulated powder containing 3 g sodium phenylbutyrate and 1 g taurursodiol that is dissolved in 250 milliliters of water and given orally or by gastric tube daily.
●Experimental therapies – While few disease-modifying drugs are available for ALS, a number of agents are under investigation. (See 'Experimental therapy' above.)
●Symptomatic management – The symptomatic management of ALS (including respiratory muscle weakness, dysphagia, nutrition, dysarthria, dyspnea, fatigue, muscle spasms, spasticity, muscle weakness, functional decline, sialorrhea, thick mucus, pain, pseudobulbar affect, psychosocial difficulties, and sleep problems) is reviewed in detail separately. (See "Symptom-based management of amyotrophic lateral sclerosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Rabia B Choudry, MD, who contributed to earlier versions of this topic review.
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