Simply Stated: Updates in Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death, often within three to five years from when the symptoms first appear. In ALS, motor neurons (nerve cells that control muscle cells) are gradually lost. As a result, the muscles they control become weak and then nonfunctional, leading to ALS symptoms.

ALS was first described by Dr. Jean-Martin Charcot in the 19th century. Today, ALS is sometimes called Lou Gehrig’s disease in the United States (US), referring to the New York Yankees baseball player who lived with the disease until his death in 1941. ALS is rare, with one recent study reporting a prevalence estimate ranging from 7.7 to 9.9 cases per 100,000 people in the US.

Symptoms of ALS

The onset of ALS can happen at any age, though most affected people begin experiencing symptoms between the ages of 40-70 years old. ALS typically affects the upper motor neurons, which are in the brain, and the lower motor neurons, which are in the brainstem and spinal cord. Motor neurons are the large nerve cells that control voluntary movement. Degeneration of the upper motor neurons can cause muscle stiffness (spasticity), slowness of movement (bradykinesia), incoordination, and poor balance when walking or standing (postural instability). Degeneration of the lower motor neurons can cause muscle weakness, shrinkage (atrophy), twitching (fasciculations), and sometimes cramps. Generally, upper and lower motor neurons are affected at the same time in ALS; however, the body site where symptoms begin, the pattern and speed of disease spread, and the degree of upper and/or lower motor neuron dysfunction can be extremely variable between different people with ALS.

Typical course of disease

A person with ALS may experience impairments of arm/leg (limb), face/head/neck (bulbar), trunk (axial), and breathing (respiratory) muscles. Most cases begin with persistent weakness or spasticity in an arm or leg. In some cases, the problem begins in the muscles controlling speech or swallowing.

Problems with mental processes (cognitive impairment) occur in some people with ALS and may come before or after the onset of upper motor neuron and/or lower motor neuron symptoms. A condition known as frontotemporal dementia (FTD), which impacts a person’s behavior and ability to produce and understand speech, is associated with ALS in 15-50% of cases. ALS can also present with pseudobulbar affect (PBA), a condition in which the affected person experiences outbursts of uncontrolled laughing, crying, or yawning.

As ALS progresses, affected people may experience a variety of additional symptoms, including constipation, dysphagia (difficulty swallowing), and incomplete eye closure and drooling due to weakened facial muscles. Some may have symptoms similar to Parkinson’s disease, such as lack of facial expressions (facial masking), tremor, bradykinesia, and postural instability. About 20-30% of people with ALS may have sensory impairments, such as reduced ability to feel pain or temperature or reduced awareness of body positioning (proprioception). In some people with ALS, pain is a side effect of muscle problems (cramps, spasticity, etc.).

ALS is relentlessly progressive. Symptoms typically spread within the location of onset (e.g. limb, bulbar) and then to other body regions in a predictable pattern. Eventually, ALS progression leads to life-threatening respiratory failure and/or dysphagia. In most cases, this occurs within 3-5 years following symptom onset, however, about 10% of people diagnosed with ALS survive for a decade or more.

For more information about the signs and symptoms of ALS, as well an overview of diagnosis, prognosis, and care management concerns, an in-depth review can be found from Siddique, et al.

Causes of ALS

Sporadic ALS presents in people with no family history of the disease and accounts for ~90% of ALS cases. The root cause of sporadic ALS is not known, although it’s generally thought that a combination of environmental exposure and genetic susceptibility may lead to the disease. Familial ALS (fALS), on the other hand, generally has a known genetic cause and presents in people with family history, accounting for ~10% of cases. Variations in more than 25 different genes and genetic loci have been associated with ALS susceptibility. C9ORF72 gene mutations (~40% in fALS cases) and SOD1 gene mutations (13-20% in fALS cases) are the most common genetic causes of fALS. fALS can be inherited in different ways, but autosomal dominant inheritance, in which one copy of a defective gene from one parent causes the disease, is the most common inheritance pattern. ALS-causing gene mutations lead to protein defects that impact the survival or function of motor neurons.

Management of ALS

Several drugs for ALS have been approved by the US Food and Drug Administration (FDA) that may help manage symptoms, reduce the rate of decline, or prolong survival. There is currently no known treatment that stops or reverses the progression of ALS. The following FDA-approved medications may be prescribed by doctors as part of a treatment plan for ALS:

• Riluzole (Rilutek) – An oral medication that may reduce motor neuron damage by decreasing levels of glutamate (molecule involved in signaling between nerve cells and motor neurons). In clinical trials, riluzole prolonged survival in people with ALS by three to six months. A thickened liquid form (Tiglutik) or dissolvable tablet (Exservan) may be prescribed for people with swallowing difficulties.
• Dextromethorphan HBr and quinidine sulfate (Neudexta) – An oral therapy approved for treatment of pseudobulbar affect.
• Edaravone (Radicava) – An antioxidant, given intravenously, that is thought to protect neurons from the damage caused by oxidative stress (toxicity due to harmful free radicals). Edaravone was shown in clinical trials to slow functional decline in some people with ALS. RADICAVA ORS is a form of edaravone taken orally or by feeding tube.
• Tofersen/BIIB067 (Qalsody) – An antisense oligonucleotide (ASO) given through spinal injection to treat people with ALS caused by mutations in the SOD1 gene (SOD1-ALS). In clinical trials, tofersen missed the primary endpoint of decreasing ALS functional changes, but met the secondary endpoint of lowering levels of plasma neurofilament light (NfL), a biomarker of nerve injury and neurodegeneration. Tofersen was approved to treat people with SOD1-ALS based on these results. The benefit of the drug is now being studied in presymptomatic people carrying the disease-causing SOD1 gene variant in the phase 3 ATLAS study.

Other medications to help manage symptoms such as muscle cramps and stiffness, excessive saliva and phlegm, pain, depression, sleep disturbances, or constipation may also be prescribed by a doctor. Additionally, supportive care provided by a multidisciplinary care team can help improve overall health and quality of life for people with ALS. An ALS care team might include physicians, pharmacists, physical, occupational, speech, and respiratory therapists, clinical psychologists, nutritionists, social workers, and home care and hospice nurses, among other professionals. This team can help create a personalized treatment plan and recommend medications and adaptive equipment to keep people with ALS comfortable, mobile, and independent for as long as possible.

Evolving research and treatment landscape

Research advances and the promise of therapeutic development on the horizon offer hope for people living with ALS. On clinicaltrials.gov, there are 74 interventional clinical trials and 72 observational trials currently enrolling people with ALS to test therapeutic candidates and collect data about disease progression, respectively.

Therapeutic candidates under investigation

Promising therapeutic strategies under active investigation for ALS include antisense oligonucleotide, small molecule, and cell-based therapies. Some drug candidates in late-stage clinical trials include:

ION636 (Ionis Pharmaceuticals, Inc.) – An antisense oligonucleotide (ASO) being investigated as a treatment for ALS caused by Fused in Sarcoma (FUS) gene defects (FUS-ALS). In FUS-ALS, toxic levels of the FUS protein cause rapid and progressive loss of motor neurons. ION636 binds to the genetic message required to make the FUS protein and reduces production of this protein. The efficacy of ION363 is being studied in the FUSION phase 3 clinical trial, which is currently enrolling.

Mastinib (AB Science) – A chemical inhibitor of tyrosine kinases, that is given orally. Mastinib is designed to block the function of specific immune cells (mast cells and neutrophils) and thus prevent the damage and degeneration of neurons in the spinal cord. The safety and efficacy of mastinib to treat ALS is being studied in a phase 3 clinical trial that is currently enrolling.

RAPA-501 (Rapa Therapeutics LLC) – A cell-based therapy in which T cells of the immune system are harvested from an ALS patient, engineered in the lab to better suppress central nervous system (CNS) inflammation, and then re-introduced into the patient as an anti-inflammatory therapy. This cell-based therapy is in a phase 2/3 clinical trial that is enrolling.

Ibudilast/MN-166 (MediciNova) – A small molecule that appears to have anti-inflammatory effects, though the mechanisms are not completely understood. The safety, efficacy, and tolerability of MN-166 in people with ALS is being investigated in the COMBAT-ALS phase 2b/3 clinical trial, which is enrolling participants.

CNM-Au8 (Clene Nanomedicine) – A stable suspension of pure gold nanocrystals designed to increase energy production from the powerhouses of the cell (mitochondria) and to protect cells against oxidative stress. CNM-Au8 can cross the blood-brain barrier and is expected to prevent nerve cell death and slow disease progression in people with ALS. Though CNM-Au8 did not meet the primary endpoint in phase 2 clinical trials, the results have been promising for a number of measures, including survival, delayed time to clinical worsening, and impact on biomarkers such as NfL (RESCUE-ALS, HEALEY, expanded access studies). Based on these findings, the sponsors are planning a large, international, multicenter, phase 3 trial of CNM-Au8 (RESTORE-ALS) to further investigate clinical outcomes.

In addition to traditional clinical trials that test single interventions, platform trials are offering flexibility in studying new therapies and interventions. Platform trial designs allow multiple interventions to be studied simultaneously or sequentially against a common control group and also allow new interventions to be added throughout the trial. Platforms trials are being employed to study ALS therapeutic candidates:

The HEALEY ALS Platform Trial (Massachusetts General Hospital (MGH)) – HEALEY ALS is the first platform trial to evaluate safety and efficacy of investigational products for treatment of ALS. It is a large, multicenter study, headed by researchers at MGH and funded by multiple partners, including MDA. The therapies under evaluation in HEALEY ALS, zilucoplan, verdiperstat, CNM-Au8, pridopidine, trehalose, ABBV-CLS-7262, and DNL343 are being compared to placebo controls in a regimen and with study conditions dictated by an overarching Master Protocol. This trial is active, but not currently enrolling participants.

Platform Trial to Assess the Efficacy of Multiple Drugs in Amyotrophic Lateral Sclerosis (ALS) (Stichting TRICALS Foundation) – This phase 3 study is testing the efficacy of multiple treatments for ALS simultaneously. Currently, one study-arm is investigating the efficacy and safety of the chemical compound lithium carbonate, which affects signaling between neurons, to treat people with ALS caused by the specific UNC13A gene mutation.

Observational studies

Several groups have established patient registries and observational studies to help collect and analyze data from people with ALS in order to improve understanding of the disease.

MDA is collaborating with Mitsubishi Tanabe Pharma America, Inc. (MTPA) on such an effort, ALS Go-Digital. This project pairs remotely collected digital data (i.e. from smartphones) with longitudinal (over the course of one year) clinical data collected from people with ALS in MDA’s NeuroMuscular ObserVational Research (MOVR) database. The goal of the study is to help determine which method of data collection may be the most useful in tracking the progression of ALS and how the results compare to commonly used assessments made by healthcare professionals in the clinic. ALS Go-Digital is actively seeking participants.

MDA commitment to End ALS

MDA is instrumental in the movement to End ALS, supporting both research and advocacy efforts. By the close of 2024, MDA will have invested more than $176M in ALS research. MDA’s annual Lou Gehrig Day, in collaboration with Major League Baseball (MLB) parks and teams, is raising awareness and funds to support the End ALS campaign. Together, strategic investments and advocacy efforts from MDA and other organizations like the ALS Association, combined with traditional funding sources such as the National Institute of Health (NIH), are helping to move the field of ALS forward.

MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about amyotrophic lateral sclerosis (ALS), open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.

Also, see MDA’s community resources for ALS to learn more.

• Download our ALS Impact Sheet to see how MDA supports families living with ALS and uses your donations to help find treatments and cures.
• Download our ALS Fact Sheet
• Watch MDA Facebook Live: ALS Care and Research Updates to learn about the latest in care and research updates related to ALS.