Rare Disease Report

Amyotrophic Lateral Sclerosis: Exploring the Current & Future Treatment Landscape

JULY 16, 2018
Rachel Lutz
Estimated to affect 5 in 100,000, the neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is known to lead to severe disability and eventual death from ventilatory failure. Despite advances made in the fight against the disease, there is no diagnostic test available to detect it, the 2 available medications to treat it provide modest benefit, and the pathogenesis of it remains incompletely understood.

In order to improve quality of life and prolong survival in patients with AML, a better understanding of the pathological mechanisms associated with the disease, and thus, new treatment options are imperative, according to a new analysis by researchers at the Mayo Clinic, in Jacksonville, Florida.

For their analysis, the researchers explored the field’s current understanding of the disease, its epidemiology, the standard care practice, FDA approved therapies and potential future therapies.

Patients with ALS, or Lou Gehrig’s disease, lose lower motor neurons and even upper motor neurons, causing spasticity, clumsiness, brisk reflexes and functional limitations, authors write. Furthermore, about half of patients experience cognitive and behavioral signs or symptoms. By monitoring extra motor movement in ALS patients, clinical care can be improved; previously, that aspect had been overlooked.

Since 2008, patients who self-identify as having ALS can participate in the US National ALS Registry, the researchers said. Because of this database, scientists are able to determine that ALS is more common in men than women, that the median survival is about 2 to 3 years from symptom onset, and older-onset might mean a faster rate of disease progression. However, variables that possibly impact ALS onset, such as genetic risk, environmental risk, smoking, athleticism, military service, head trauma, as well as other various factors, are still widely unknown, according to the report.

Although pathogenesis for ALS remains unknown, understanding has increased within the last decade, which has brought about new characterizations for the disease. For example, learning more about a protein called TDP-43 showed that it is likely the primary component in ALS, leading to neuronal dysfunction and eventually cell death. The interaction between TDP-43 and RNA-binding proteins can promote aggression and disruption of neuronal homeostasis, according to the authors.

With no true diagnostic test for ALS, the researchers described a series of steps to clinically diagnose it: a history of progressive, painless weakness, and an examination of upper and lower motor neuron dysfunction. At first, the initial diagnosis may be uncertain, but after the development of additional symptoms—such as a spastic pattern of speech or a foot drop caused by upper and lower motor neuron dysfunction, respectively—the diagnosis may “be established with greater certainty,” the authors write.

Generally, most treatments for the disease employ a multidisciplinary approach for patient care. Telemedicine is also an emerging therapy, in addition to the other approaches, the researchers said.

Drug therapies have been limited to riluzole for the most part, which is generally well-tolerated but has a survival benefit of about three months, according to most studies. Rare Disease Report® recently covered a study that demonstrated riluzole’s effectiveness in prolonging stage 4 of ALS.

“Additionally, our finding that riluzole works at the end stage of ALS lead to a greater understanding of both drug and disease mechanisms, both of which is currently unclear,” study author Dr. Ton Fang, iBSc (Hons) said at the time. “Our research also improves the awareness for using staging to determine the effects of treatment in neurodegenerative diseases, where TNM staging is already widely used in cancer research.”

Addressing symptoms is another important part of treating the disease, and the use of educational methods and recurrent reminders may improve compliance for clinical interventions, according to the researchers.

Though depression and anxiety are not commonly seen in ALS patients, about one-quarter to half of the patients may develop pseudobulbar effect. This can be treated with dextromethorphan and quinidine, approved by the US Food and Drug Administration (FDA) in 2010, the authors said. Other useful treatments are support groups and caregivers.

The researchers write that the leading cause of death for ALS patients is ventilator failure; as such, drugs such as opiates and benzodiazepines should be avoided due to their reducing effect on respiratory drive. Additionally, impaired swallowing ability can lead to aspiration and poor nutrition. Gastrostomy placement is standard to achieve proper nutrition, but the researchers said it may not prolong patient survival.

“The patients’ individual goals of care are important, and treatment plans should be tailored with these goals in mind and using interventions acceptable to the patient,” the study authors wrote, adding that patients often have questions about physician-assisted suicide.

“Most patients with ALS will die of their ALS, and many will have questions regarding this process,” the authors write. “Should the patient want this type of information, factual and compassionate information regarding the dying process can help demystify it and reduce anxiety.” 

Edaravone was approved for ALS treatment by the FDA in 2017, to be delivered by intravenous infusion in cycles of daily dosing over the course of two weeks, followed by two weeks without drugs. It is not typically covered by many US insurance companies. However, the drug is currently being developed in an oral form, which should improve the ability of insurance companies to cover it, according to the authors.

Over the past few years, stem cell-based therapies for the potential treatment of ALS and other neurodegenerative diseases have generated considerable excitement. Currently, stem cell-based therapies are being evaluated in phase 1, 2, and 3 clinical trials, using several different cell types. These approaches are being developed to protect surviving motor neurons via paracrine effects, not to replace motor neurons that have died.

Mesenchymal stromal cells (MSCs) are being used as an autologous stem cell therapy for ALS, as these cells are capable of secreting neurotrophic factors as well as modulating the immune system—both of these capabilities have been shown to slow the course of the disease when tested in animal models. MSCs have a good safety profile, according to the authors, but none of the early-phase studies have been powered to prove efficacy; however, the trials have suggested that a subset of patients with ALS may respond well to this therapy.

In the future, the researchers plan to further examine other agents, such as tyrosine kinase inhibitor masitinib as a potential treatment of the disease. Filed for approval in Europe after positive studies, the effect of masitinib is thought to fall within the range of riluzole or edaravone; however, more research needs to be done to validate this.

“Current treatment strategies are otherwise largely palliative, aiming to provide better life quality and longer survival, with assisted ventilation being the single most powerful approach,” the authors conclude. “With a better understanding of the underlying genetic causes and the pathogenesis of ALS, many novel treatment approaches are in development, hopefully leading to more effective treatments in the near future.”
 

Stay informed on the latest rare disease news and developments by signing up for our newsletter.
Copyright © RareDR 2013-2018 Rare Disease Communications. All Rights Reserved.