Current ALS Clinical Trials

The investigational drug LY4256984 is an antisense oligonucleotide (ASO). ASOs are small pieces of genetic material that can attach to RNA, the molecule that carries instructions for making proteins, blocking its ability to make proteins or perform other functions. Qalsody, a therapy approved in Canada to treat SOD1-ALS, is an ASO.

LY4256984 is designed to target the UNC13A gene, which is important for communication between neurons (a process called synaptic function). In almost all people living with ALS (over 97%), a protein called TDP-43 ends up in the wrong place inside the cells. This causes problems with RNA processing, including something called mis-splicing, where the RNA molecule gets cut and joined incorrectly. When this happens to UNC13A, the cell makes faulty RNA and less of the normal protein, which impacts synaptic function. LY4256984 is designed to bind to the UNC13A RNA to prevent this mis-splicing, thereby reducing harmful RNA pieces, restoring normal UNC13A protein levels, and potentially provide better support to motor neurons.

This Phase 1 study will enroll 32 participants living with ALS, who will be randomly assigned to receive the experimental therapeutic LY4256984 or placebo via intrathecal injection (lumbar puncture). Measures will be taken over the span of 253 days from the first dose. The study will evaluate the safety and exploratory markers of LY4256984 by measuring adverse events, optimal dosing, and the incidence of abnormalities in clinical tests.

The study page does not state the exact duration of the trial. Please speak to your ALS neurologist for further details.

*This study is not yet recruiting in Calgary, Edmonton, London, and Toronto.

The blood-brain barrier (BBB) is a protective layer that controls what can pass from the bloodstream into the brain, allowing essential nutrients in while blocking out harmful substances like toxins and bacteria. While this barrier is crucial for keeping the brain safe, it also makes it difficult for most drugs to reach the brain, which poses a challenge for treating ALS.

Researchers at the Sunnybrook Health Sciences Centre have been testing a new technology to noninvasively deliver treatments across the BBB using a focused ultrasound (FUS) procedure and other techniques that open small spaces in the barrier, allowing treatments to cross into the brain. In this trial, they aim to evaluate the safety and biological effects of these techniques by administering an immunoglobulin (IVIG) treatment to the brain. IVIG is a therapy made from antibodies collected from donated plasma. It’s commonly used to treat autoimmune and inflammatory conditions because it can help regulate abnormal immune responses.

This Phase 1 study will enroll 6 participants living with ALS, without a placebo group. Participants will undergo two doses of IVIg, 2 weeks apart, with the second dose being accompanied by a single BBB opening procedure using focused ultrasound. Follow-ups will occur over the span of 6 months from the first dose. The study will assess the safety and feasibility of both the IVIG treatment and the BBB opening procedure, as well as collecting other measures such as neurofilament light chain (NfL) levels, inflammatory markers, and ALSFRS-R scores.

In ALS, immune responses and neuroinflammation have long been associated with the disease, but no therapeutic has yet been able to successfully regulate this system to improve disease progression. COYA 302 is an investigational therapy that combines two components designed to target immune imbalance:

• Low dose interleukin-2 (IL-2): Helps boost regulatory T cells (Tregs), which release substances that can regulate inflammation. IL-2 is a molecule naturally produced in the body, called a cytokine.
• CTLA-4 Ig (or DRL_AB): Designed to calm immune cells such as monocytes and macrophages, which can trigger excessive or prolonged inflammation that causes damage in the body.

By restoring balance in the immune system, investigators believe COYA 302 may help to slow ALS progression.

This Phase 2 study will recruit 120 participants, who will be randomly assigned to receive the experimental therapeutic COYA 302 or placebo via subcutaneous injection (small injections under the skin) for 5 consecutive days every other week. Participation in the study will last up to 6 months, followed by a blinded active extension phase (EXT), in which all participants will be eligible to receive one of two different doses of COYA 302 for an additional 6 months. The study will evaluate exploratory markers of COYA 302 by measuring changes in the ALSFRS-R scale, serum neurofilament light chain (NfL), survival, and other respiratory measures.

View the ALS Clinical Trials Unboxed webinar on VHB937 here.

The experimental therapeutic VHB937 is a lab-made antibody designed to help certain immune cells in the brain, called microglia. It activates a protein called TREM2 on the surface of these cells. This activation is thought to enhance microglial function, including their ability to clear damaged cells and harmful waste, potentially protecting motor neurons, the brain cells responsible for voluntary muscle control, from damage. Through this mechanism, researchers believe VHB937 could help protect motor neurons, reduce inflammation, and have a positive impact on disease progression.

This Phase 2 study will recruit 225 participants, who will be randomly assigned to receive the experimental therapeutic VHB937 or a placebo via intravenous injection (IV). Participants with ALS need to be within two years of ALS symptom onset to be eligible. The study will last up to 40 weeks, followed by an open label extension, where all participants will have the chance to receive VHB937. The study will evaluate the efficacy of the therapeutic on survival and the delay of permanent assisted ventilation (PAV). Additional measures include changes in the ALSFRS-R score, respiratory function, biomarker concentration (NfL), as well as assessing adverse events and drug metabolism.

View the ALS Clinical Trials Unboxed webinar on AMX0114 here.

Antisense oligonucleotides (ASOs) are short, synthetic strands of DNA or RNA designed to bind to specific RNA molecules in the body. This blocks the ability of the RNA to make a protein or work in other ways. The experimental therapeutic AMX0114 is an ASO targeting the mRNA of a protein called calpain-2, a calcium-dependent cysteine protease. Calpain-2 cleaves proteins inside cells, and its overaction has been linked to the degeneration and death of motor neurons, the brain cells responsible for voluntary muscle control. By reducing the levels of calpain-2, investigators believe the drug can slow down disease progression and neuronal degeneration.

This Phase 1 study will recruit 48 participants, who will be randomly assigned to receive the experimental therapeutic AMX0114, or placebo via intrathecal injection (lumbar puncture) once every 4 weeks. Participation in the study will last up to 145 days. The study will evaluate the safety and exploratory markers of AMX0114 by measuring adverse events, optimal dosing, the incidence of abnormalities in clinical tests, and biomarker measures.

View the ALS Clinical Trials Unboxed webinar on prosetin here.

In our cells, the endoplasmic reticulum (ER) is an important compartment responsible for protein production and folding, and it plays an essential part in responding to protein misfolding and aggregation, hallmarks of ALS. The overloading of the ER can increase cellular stress and contribute to misfolded proteins and aggregates, leading to inflammation and damage to nerve cells. The experimental therapeutic prosetin is a molecule designed to inhibit a protein called mitogen-activated protein kinase kinase kinase kinase (MAP4K) in the brain. Investigators believe this lessens ER stress, reducing inflammation and promoting neuronal survival.

This Phase 1 study will recruit 24 participants, who will be randomly assigned to receive either different doses of the experimental therapeutic prosetin, or placebo orally for 14 days. After this two-week timeframe, the study will have an extension period where all participants will receive prosetin. Participation in the study will last up to approximately 54 weeks. The study will evaluate the safety and exploratory markers of prosetin by measuring adverse events, optimal dosing, and the incidence of abnormalities in clinical tests.

Due to the specificity of this treatment, this clinical trial is only open to individuals with a variant (mutation) in the SOD1 gene.

Variants (mutations) in a gene called Superoxide dismutase 1 (SOD1) are known to contribute to ALS onset and disease progression. The gene is believed to gain a toxic function that is damaging to the nerve cells that control voluntary muscles, called motor neurons. The experimental therapeutic ALN-SOD is an RNA interference therapeutic, which is a class of drugs that can silence genes. By silencing the abnormal SOD1 gene in people living with SOD1-ALS, researchers theorize this can slow down or stop disease progression.

This Phase 1 study will recruit 42 participants, who will be randomly assigned to receive either different doses of the experimental therapeutic ALN-SOD, or placebo by intrathecal (IT) injection. After four weeks, the study will have an extension period where all participants will receive ALN-SOD. The study will evaluate the safety and effectiveness of ALN-SOD by measuring adverse events, biomarker measures, and concentration of the drug and presence of antibodies against the drug over time. The presence of antibodies could make the drug less effective or lead to side effects.

View the ALS Clinical Trials Unboxed webinar on ALN-SOD here.

The neuromuscular junction (NMJ) is the site where motor neurons connect to muscle fibers, allowing signals from the brain to pass to muscles. Many researchers believe that one of the earliest events in ALS is the disconnection of motor neurons from muscles at the NMJ, contributing to disease onset and progression.

A cell receptor called muscle-specific kinase (MuSK) plays an important role in maintaining healthy NMJs. Impaired MuSK function can lead to damage to the NMJs and muscle weakness. ARGX-119 is an agonist antibody that can activate MuSK functions in the body. By activating MuSK signaling in this way, researchers theorize that this can help stabilize and protect NMJs in people living with neuromuscular diseases.

This Phase 2 study will recruit 119 participants, who will be randomly assigned to receive either different doses of the experimental therapeutic ARGX-119, or placebo intravenously. After these doses, the study will have an extension period where all participants will receive ARGX-119. Participation in the study will last up to approximately 25 months. The study will evaluate the safety and effectiveness of ARGX-119 by measuring changes in muscle function, adverse events, and the presence of antibodies against the drug over time. The presence of antibodies could make the drug less effective or lead to side effects.

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.

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.

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.