Disease-modifying treatment of amyotrophic lateral sclerosis
Rabia B Choudry, MD
Nestor Galvez-Jimenez, MD, MSc, MHSA, FACP
Merit E Cudkowicz, MD, MSc
Section Editors:
Jeremy M Shefner, MD, PhD
Ira N Targoff, MD
Deputy Editor:
April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 28, 2018.

INTRODUCTION — Amyotrophic lateral sclerosis (ALS), first described by Charcot in the 19th century [1], 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 [1].

The existing and experimental disease-modifying pharmacologic treatment of ALS will be reviewed here. The symptomatic management and the clinical features and diagnosis of ALS are discussed separately. (See "Symptom-based management of amyotrophic lateral sclerosis" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

RILUZOLE — Riluzole is the only known drug to have any impact on survival in ALS [2]. The evidence that riluzole is beneficial comes from two landmark clinical trials [3,4]:

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) [3]. 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 study, 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 [4]. 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).

Given these data, we recommend riluzole 50 mg twice daily for patients with ALS.

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 [5]. However, its precise mechanism of action in ALS is unclear [6].

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 [7]. The AAN recommended that riluzole should be offered to slow disease progression in patients with ALS.

An earlier AAN practice advisory on the treatment of ALS noted that patients most likely to benefit from treatment with riluzole include those with the following clinical features [8]:

Definite or probable ALS by El Escorial criteria [9], in whom other causes of progressive muscle atrophy have been ruled out

Symptoms present for less than five years

Vital capacity (VC) greater than 60 percent of predicted

No tracheostomy

Patients with these characteristics are likely to be similar to patients eligible for inclusion in the randomized trials that established the benefit of riluzole.

Patients for whom no randomized data support the use of riluzole but expert opinion suggests potential benefit include those who have [8]:

Suspected or possible ALS by El Escorial criteria

Symptoms present for more than five years

VC 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

Riluzole 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. 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 [10]. 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 [11]. 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 [12]. Liver function tests are indicated monthly for the first three months of riluzole treatment and every three months thereafter.

EDARAVONE — Edaravone is a free radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of ALS. Edaravone was found to slow functional deterioration in some patients with ALS, as observed in randomized controlled trials:

An earlier 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 [13]. 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 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 [13,14].

A subsequent controlled trial enrolled 137 Japanese subjects with early-stage ALS who were selected to match the subset of patients 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) [14]. Subjects 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 [14,15]. In addition, subjects assigned to edaravone experienced less decline on the ALS Assessment Questionnaire (ALSAQ-40).

Edaravone was approved in 2015 for the treatment of ALS in Japan and Korea, and received US Food and Drug Administration (FDA) approval for all people with ALS in May 2017 to treat patients with ALS in the United States [16]. While the evidence for the benefit of edaravone is clearest in patients with early ALS, as defined in the pivotal trial [14,17], there is no reason to believe that the population evaluated in that trial is biologically distinct from the greater ALS population. Therefore, we suggest edaravone treatment as an adjunct to riluzole for all patients with ALS. Additional data from registries and follow-up studies are needed to clarify the utility of edaravone for people in different stages of the illness.

Edaravone dosing and adverse effects — Edaravone 60 mg is given by intravenous infusion over 60 minutes [18]. Treatment is started with daily infusion for 14 days, followed by 14 days off treatment. Subsequent treatment cycles involve daily edaravone 60 mg infusions on 10 days within a 14-day period, followed by 14 days off treatment. The estimated yearly cost of edaravone in the United States is approximately $146,000.

The most frequent adverse reactions among subjects treated with edaravone in clinical studies were injection-site contusion, gait disturbance, and headache [16]. Edaravone contains sodium bisulfite, which may cause allergic reactions including asthmatic episodes in susceptible individuals [18]. 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'.)

EXPERIMENTAL THERAPY — While multiple drugs have shown promise in preclinical in vitro and in vivo models of ALS, they have failed to show efficacy in human trials. These include glutamate antagonists other than riluzole, neurotrophic factors, antiapoptotic agents, antioxidants other than edaravone, and immunomodulatory drugs. Clinical trials have found no benefit for ceftriaxone [19], celecoxib [20], ciliary neurotrophic factor [21], coenzyme Q10 [22], creatine [23,24], dexpramipexole [25], gabapentin [26,27], lamotrigine [28], lithium [29-32], minocycline [33], ozanezumab [34], recombinant insulin-like growth factor type I (IGF-I) [35,36], talampanel [37], TCH346 [38], topiramate [39], valproic acid [40], or verapamil [41].

Other investigational approaches are discussed below.

Animal models — Several animal models have been developed to investigate the pathogenesis and treatment of ALS. Earlier studies used pure motor neurons cultured in vitro [42]. In vitro models of cell death based on superoxide dismutase (SOD1) enzyme dysfunction were developed after the discovery of the Cu/Zn SOD1 gene abnormalities in familial ALS [43,44], and several mouse and rat models expressing mutant forms of the SOD1 gene exist [45]. In addition, transgenic rodent models of ALS were developed based upon mutant forms of the human TDP-43 gene (TARDBP) [46-48]. The experimentally induced mutations G93A, G37R, and G85R in the transgenic mouse models have phenotypes similar to human ALS [49]. There are also naturally occurring mouse models including the motor neuron degeneration (Mnd), progressive motor neuropathy (pmn), and wobbler, and models of motor neuron disease in flies, worms, and induced pluripotent stem cell (IPSC) motor neurons [50-54].

The transgenic SOD1 mouse model is considered the most accurate representation of the disease process. However, the utility of this animal model for screening potential human ALS treatments is not established. A number of investigators have challenged its validity, since some experimental therapies that are effective in this model have not proven effective in human trials. Nevertheless, limitations in these trials related to dose range and sample size render direct comparison of animal with human studies quite speculative.

Neurotrophic factors — Trials utilizing IGF-I and other neurotrophic factors for ALS have been unsuccessful [21,35,36]. The limitations and short-comings of these agents are related to unfavorable pharmacokinetics, bioavailability, and dose-limiting toxicities, in addition to the possibility that antibody inactivation may occur. However, alternative methods of drug delivery, such as gene therapy or mesenchymal derived cells modified to deliver growth factor, may be warranted. (See 'Gene therapy' below.)

Antioxidants — 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 [55]. In a subsequent 18-month trial, subjects were randomly assigned to either megadose vitamin E at 5000 mg/day or placebo [56]. 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.

In another 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 [57]. However, there was a beneficial trend in survival for the patients with limb-onset disease.

Current and future trials — A number of agents are under investigation for the treatment of ALS, including the following [58-60]:

Antisense oligonucleotide therapy for SOD1-associated familial ALS (see 'Gene therapy' below)


Arimoclomol for familial ALS (see 'Arimoclomol' below)

Fingolimod [61]


Memantine [62]

Mexiletine [63]

NP001 [64]

Retigabine [65]

Stem cell treatments [66-69]

Tamoxifen [70]

Tirasemtiv (see 'Tirasemtiv' below)

Tocilizumab [71,72]

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.

Some agents currently in trial are described below.

Arimoclomol — Heat shock proteins are involved in protein repair, and thus are cytoprotective. Motor neurons appear to have a high threshold for activation of the heat shock protein pathway, and SOD1 gene mutations may contribute to reduced antiapoptotic capability [73]. Treatment of G93A mice with arimoclomol, a coinducer of heat shock proteins, delayed disease progression and improved survival by 22 percent [74].

A trial of arimoclomol in 38 people with SOD1-mutant ALS found that a dose of 200 mg three times daily was safe and well tolerated for up to 12 months [75]. Secondary efficacy outcomes suggested possible clinical benefit; however, confidence intervals were wide due to the small number of patients enrolled. Larger studies using higher doses in a broader patient population are under consideration.

Gene therapy — Previous clinical trials with neurotrophic factors have shown equivocal to negative results (see 'Experimental therapy' above). Research in a transgenic mouse model found that IGF-I can be delivered directly to respiratory and motor limb muscles to target the affected motor neurons by using the retrograde transport ability of adeno-associated virus (AAV) [76]. IGF-I delivered by this vector delays disease onset and prolongs survival by 30 percent in the preclinical model and 18 percent in the postsymptomatic model in the SOD1-mutant mouse model.

In a similar method, glial cell line-derived neurotrophic factor (GDNF) gene was injected into lower-extremity muscles of a G93A transgenic mouse using a replication defective adenoviral vector [77]. Larger motor neurons were seen in the injected muscles, suggesting gene therapy may delay progression in ALS.

Vascular endothelial growth factor (VEGF) is needed for angiogenesis and has been implicated in neuroprotection [78,79]. Researchers have shown that low levels of VEGF in transgenic mice can cause an ALS-like syndrome. Furthermore, intramuscular delivery of VEGF has shown delayed onset and prolonged survival in SOD1 mice.

In a study of intracerebroventricular delivery of VEGF gene therapy in transgenic rats, VEGF delayed disease onset, improved motor performance, and delayed the onset of paralysis [80]. This particular route was chosen over intrathecal delivery because of a speculated improved effect on bulbar and cervical motor neurons rather than motor neurons in the lumbar cord. VEGF gene therapy will likely be investigated in human trials in the near future.

Another approach to gene therapy employs antisense oligonucleotides to downregulate or silence mutant genes. 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.

In a preliminary study, continuous intraventricular infusion of antisense oligonucleotides to SOD1 reduced both SOD1 protein and mRNA levels throughout the rat brain and spinal cord [81]. In addition, this treatment significantly slowed disease progression when initiated prior to disease onset in a rat model of ALS caused by an SOD1 mutation. A preliminary human trial of an antisense oligonucleotide to SOD1 (ISIS 333611) found that the drug was well tolerated and achieved predicted levels in cerebrospinal fluid and plasma [82]. Other antisense oligonucleotide studies are ongoing.

Tirasemtiv — Tirasemtiv is a fast skeletal muscle troponin activator that works by increasing the sensitivity of the sarcomere to calcium, which amplifies the force of muscle contraction when motor nerves are stimulated at submaximal rates [83-85]. The drug was developed as a therapy to increase muscle strength for patients with neuromuscular disease such as ALS [83]. In an SOD1 transgenic mouse model of ALS, tirasemtiv significantly increased muscle strength and performance [86]. Findings from early short-term human clinical trials suggested beneficial effects of tirasemtiv for measures of function, strength, and endurance [87-89]. However, a completed phase III trial failed to reach its primary endpoint [90]. Significant issues regarding tolerability of tirasemtiv were noted, resulting in differential dropout and dose reductions in the active treatment groups versus placebo. A drug with a similar mechanism but hopefully better tolerability (CK-2127107) is now in a phase 2 trial.


Disease-modifying treatment options for amyotrophic lateral sclerosis (ALS) are limited. Riluzole is the only drug to have any impact on survival, slowing ALS progression to a modest degree. (See 'Riluzole' above.)

For patients with ALS, we recommend treatment with riluzole 50 mg twice daily (Grade 1A). 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. (See 'Riluzole' above and 'Guidelines' above and 'Riluzole dosing and adverse effects' above.)

For patients with ALS who have a disease duration of two years or less, are living independently, and have an FVC ≥80 percent, we suggest treatment with edaravone (Grade 2B). We also suggest edaravone for patients with more advanced ALS (Grade 2C). (See 'Edaravone' above.)

While few disease-modifying drugs are available for ALS, a number of agents are under investigation. (See 'Experimental therapy' above.)

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".)

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