Current ALS Clinical Trials

A hallmark feature of ALS, thought to occur even before symptoms appear, is the overexcitement (or hyperexcitability) of motor neurons in the brain. This change occurs at the cellular level and cannot be noticed by those who experience it, but researchers have found evidence of hyperexcitability in both electrical recordings from the brain and markers in the cerebrospinal fluid of people with ALS. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that uses a magnetic field to stimulate and modulate the excitability of nerve cells. One method, known as continuous theta burst stimulation (cTBS), is believed to safely reduce this hyperexcitability by delivering a high number of magnetic pulses to a targeted area of the brain in a short period of time. In this pilot study, 15 participants will undergo the procedure over 5 days. Researchers will monitor participants to ensure the technique is safe and well-tolerated and assess any changes in corticospinal excitability and biological markers at one week and three weeks after the treatment.

In ALS, the accumulation of abnormal proteins is thought to contribute to disease progression. Previous research has shown that the pathways responsible for regulating healthy protein levels and clearing abnormal proteins can be dysregulated in the disease. This dysregulation contributes to abnormal protein aggregation inside cells, disrupting normal cellular function. VRG50635 is a small-molecule inhibitor that reduces the activity of a molecule called PIKfyve. Reduction in PIKfyve activity is believed to promote pathways for clearing these toxic and aggregated proteins inside cells. In the lab, VRG50635 has been shown to extend survival in cell and animal models of ALS. This Phase 1 study will investigate VRG50635 in a clinical setting by recruiting 50 participants. The study is open-label with no placebo group, meaning all participants will receive the active drug for up to 80 weeks. Researchers will monitor participants to ensure the drug is safe, determine the appropriate dosage, learn how the body metabolizes the drug, and look for exploratory indications of its biological effects on ALS to determine the next steps.

View the ALS Clinical Trials Unboxed webinar on VRG50635 here.

Evidence suggests that the gut microbiome may play a role in susceptibility to various diseases, including those affecting the brain. Probiotics are friendly, live bacteria that benefit the digestive system and are being explored for their potential effects on a range of diseases, including obesity, colorectal cancer, cardiovascular disease, and ALS. In worm models of ALS, the probiotic formulation Lacticaseibacillus rhamnosus HA-114 was shown to help prevent neurodegeneration and appeared to aid lipid metabolism within cells. Proper lipid metabolism is crucial for maintaining normal cellular energy levels and function. Further work confirmed the effects in ALS model mice before moving to human clinical trials. This Phase 2 study will recruit 150 participants, who will be randomly assigned to receive either the dietary supplement PROBIO_HA114 or a placebo orally for 24 weeks. The study will evaluate the safety and effectiveness of PROBIO_HA114 by measuring changes in a variety of biological measures, such as lipidomic and metabolite profiles, as well as the ALS Functional Rating Scale-Revised (ALSFRS-R) score.

The neuromuscular junction (NMJ) is the site where motor neurons connect to muscle fibers, allowing signals from the brain to pass to muscles. Glial cells, which support neurons, play a crucial role in maintaining the stability and repair of this junction. Many researchers believe that one of the earliest events in ALS is the disconnection of motor neurons from muscles at the NMJ, along with inadequate glial cell repair. This Phase 2 trial will investigate the effects of the drug darifenacin on the NMJs of people living with ALS. The hypothesis is that darifenacin can help maintain this essential connection between neurons and muscles by targeting glial cell repair, thereby improving muscle control and function while reducing muscle loss. The study will recruit 30 participants, who will be randomly assigned to receive either the active drug or a placebo orally for 24 weeks. Researchers will monitor participants to ensure the drug’s safety and determine the appropriate dosage. They will also assess muscle strength, respiratory function, and changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) score.

View the ALS Clinical Trials Unboxed webinar on darifenacin here.

The progressive paralysis experienced by people living with ALS can eventually make communicating with others difficult as the ability to gesture and speak lessens with the weakening of the muscles. To help improve quality of life for people affected by ALS, researchers from the Ottawa Hospital Research Institute are testing the safety of a new assistive device that uses brain-computer interface (BCI) technology to help people who have motor impairments to communicate. This device can convert brain signals into single letters on a computer screen, allowing people to spell words simply with their thoughts. The technology requires surgical placement of two sensors into the areas of the brain that support motor and cognitive function. Researchers will be monitoring the two participants to ensure that the procedure is safe, and to assess the ability of this technology to support effective communication and improve quality of life.

Ibudilast (also referred to as MN-166) is an experimental therapy being developed to treat ALS. This broad target drug is thought to reduce the activity of immune cells in the brain, thereby supressing inflammation. It is also believed to promote the production of neurotrophic factors which play a role in the growth and survival of motor neurons. The Phase 2b/3 COMBAT-ALS clinical trial will enroll 230 participants living with ALS and last 12 months. Researchers will monitor participants to ensure that the drug is safe. Researchers will also evaluate the impact of ibudilast on the progression of ALS by evaluating changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) score, as well as muscle strength, quality of life, and respiratory function. Ibudilast will be taken by mouth in combination with a dose of riluzole. Researchers believe the anti-inflammatory and neuroprotective characteristics of ibudilast make it a promising treatment option for ALS.

To learn more, please click here to view a webinar hosted by the study sponsor, MediciNova.

Antibodies are proteins that are produced by the immune system to protect the body against foreign invaders like bacteria and viruses, and work by binding to specific proteins on the harmful agents and triggering their removal and/or destruction. In this Phase 2 clinical trial, researchers will be testing the safety of a human antibody (called AP-101) designed to target an ALS-linked protein called SOD1. Evidence suggests that the misfolding of SOD1 in cells can cause the protein to take on a toxic gain of function. Researchers are hopeful that targeting this protein may represent a promising strategy for the treatment of ALS. A previous Phase 1 study found the drug to be safe and well-tolerated at the tested doses. In this follow-up study, researchers expect to enroll 63 participants who will be randomly divided to either receive the active drug (AP-101) or placebo intravenously (IV), for 48 weeks. Both individuals with familial, SOD1-ALS and sporadic disease will be eligible to participate. Researchers will monitor participants to ensure that the drug is safe, identify any side effects, determine the appropriate dosage, and learn more about how the body breaks down the drug internally.

BIIB067 (also referred to as tofersen) is an antisense oligonucleotide (ASO) that is being studied to treat a familial form of ALS linked to mutations in the SOD1 gene. As a result of mutation, SOD1 is believed to gain a toxic function that is damaging to the nerve cells that control voluntary muscles, called motor neurons. Tofersen is designed to decrease production of SOD1 which researchers hope will lead to preservation of motor neurons and slowed progression of the disease. It is delivered into the spinal fluid through a procedure known as an intrathecal injection. Although a previous Phase 3 clinical trial studying tofersen was not able to demonstrate a statistically significant difference in ALSFRS-R score between the active drug and placebo groups over the 6-month study period, treatment with tofersen did show signs of clinical effect across multiple measures. This Phase 3 clinical trial, called ATLAS, is the first of its kind as it will be enrolling participants with a SOD1 mutation who are considered to be presymptomatic (e.g., do not yet show overt signs of the disease), but have an elevated biomarker indicating the sub-clinical triggering of ALS. The goal of this study is to determine whether presymptomatic treatment with tofersen can delay the onset of clinical ALS diagnosis and slow functional decline thereafter. Participants in the study will be treated for up to two years.

Withania somnifera is a herb whose extracts have been in use for centuries in Indian, Chinese and Arabic traditional medicines. Extracts were reported to have anti-inflammatory, antitumor, anti-stress, antioxidant, immunomodulatory, and rejuvenating properties. There is a growing body of evidence suggesting that Withania somnifera extract may also have neuroprotective effects. In previous studies using mouse models of ALS (1,2), researchers found that treatment with Withania somnifera increased lifespan and improved motor performance. The positive effects observed were thought to be due, in part, to Withania somnifera’s anti-inflammatory properties as evidenced by reduced activation of NF-κB, which plays a key role in regulating the immune response. This Phase 2 clinical trial is expected to enroll 75 participants, who will be given Withania somnifera extract, or placebo, by mouth over an 8-week period. Researchers will monitor participants to ensure that the drug is safe and determine the appropriate dosage

Abnormalities in a protein called TDP-43 are present in approximately 97 percent of all ALS cases. Preclinical studies have shown that when the amount of functional TDP-43 is decreased within cells, the level of another protein, STMN2, is substantially decreased. Patient tissues analyzed by researchers also showed that STMN2 levels are lower than expected specifically in motor neurons. These findings support the idea that a reduction in STMN2 resulting from TDP-43 dysfunction contributes to ALS and suggest that methods to preserve the levels of STMN2 within motor neurons may have a therapeutic benefit. QRL-201 is a genetically targeted therapy that aims to restore normal STMN2 levels in people living with ALS. This Phase 1 study will enroll 64 participants who will be randomly assigned to have either the active drug (QRL-201) or placebo delivered into the spinal fluid through a procedure known as an intrathecal injection. Researchers will monitor participants to ensure that the drug is safe, determine the appropriate dosage, and learn more about how the body breaks down the drug internally.

Mutations in the FUS gene are a known genetic cause of ALS, with most cases of juvenile-onset ALS linked to this gene. It is believed that these mutations result in the production of abnormal FUS proteins, which are prone to create toxic clumps in cells leading to nerve damage.

ION363 is an antisense therapy that targets and binds to FUS messenger RNA (mRNA), the molecule that carries the information required to produce FUS protein in cells. It is delivered into the spinal fluid through a procedure known as an intrathecal injection. Researchers are hopeful that ION363 will lower the levels of abnormal FUS protein in cells and ultimately slow the progression of disease.

This Phase 3 clinical trial will enroll approximately 64 participants and be conducted in two-parts. In Part 1, participants will be randomized in a 2:1 ratio to receive either ION363 or placebo (via intrathecal injection) for a period of 29 weeks. In Part 2, all participants will receive ION363 for a period of 77 weeks. The effectiveness of ION363 will be studied using measures of functional impairment, quality of life and survival.