Treatment trials

The Phase 2/3 trial (CENTAUR) to evaluate the safety and efficacy of AMX0035 in 137 participants is COMPLETED.

AMX0035 is a combination therapy designed to reduce neuronal death through blockade of key cellular death pathways originating in the mitochondria and endoplasmic reticulum (ER). This clinical trial was designed to demonstrate that treatment is safe, tolerable, and able to slow decline in function as measured by the ALSFRS-R. The trial will also assess the effects of AMX0035 on muscle strength, vital capacity, and biomarkers of ALS including markers of neuronal death and neuroinflammation.

AMX0035 was investigated in a double-blind Phase 2/3 safety and efficacy trial in 137 ALS patients diagnosed within 8 months of enrolling and with rapidly progressive disease. At 25 clinical centers across the U.S., patients were randomly assigned to either AMX0035 or placebo, given twice daily for six months. While in the trial, they could continue with their stable riluzole treatment.

After completing this trial, all were given the option to enter an open-label extension study and receive the experimental treatment for an additional 30 months. About 90% of patients, around 120 people, opted to enter in CENTAUR-OLE (NCT03488524).

Amylyx announced in December 2020 that CENTAUR met its primary goal, with patients randomized to AMX0035 experiencing a slower decline in existing abilities, including speech, swallowing, dressing and hygiene, compared with those on a placebo.

Read the summary of results on our MND Research Blog:
- Virtual Symposium: Update on AMX0035 CENTAUR and open-label extension trials
- Latest news from the CENTAUR trial puts AMX0035 in the mix
- Update on the CENTAUR trial: open label extension data

Find out more on clinicaltrials.gov.

AP-101 is a human monoclonal antibody that targets, and therefore seeks to reduce or eliminate, misfolded superoxide dismutase-1 (SOD1). This defective protein has been established as one of the causes of familial ALS. 

AL-S Pharma AG, a biotech company jointly founded and financed by Neurimmune and TVM Capital Life Science, has enrolled the first patient in its Phase 1 clinical trial assessing the safety and tolerability of AP-101. The multi-center, open-label, study is expected to recruit 18 participants from five clinical sites in Canada. Find out more about this trial at clinicaltrials.gov.

The experimental therapy has received orphan drug designation from the U.S. Food and Drug Administration, the European Medicines Agency (EMA) and Swissmedic for the treatment of ALS. 

CuATSM (Copper ATSM) is a candidate MND drug that is being investigated by the Collaborative Medicinal Development company for its effects of slowing down progression and improving respiratory and cognitive function. The drug is thought to work by delivering copper to cells where the cell's energy batteries, mitochondria, have been damaged, allowing for selective delivery of the drug (i.e. to only those cells that have been damaged).

The Phase 1 results were first announced in December 2018, showing that the treatment was safe and well-tolerated, with some beneficial effect observed. You can read more about the results in our blog article.

Find out more about this trial at clinicaltrials.gov

Phase 2/3 has begun recruiting participants in September 2019 to explore whether the drug is beneficial to people with MND, in a larger cohort of people. The trial (NCT04082832) is aimed at evaluating the efficacy and safety of CuATSM. The multicenter, randomized, double-blinded, placebo-controlled study is planning to recruit up to 80 ALS patients at four clinical sites in Australia.

Find out more about this trial at clinicaltrials.gov

This Phase 2/3 trial (called FAIRS-ALS II) is currently RECRUITING in France.

The alteration of iron metabolism is reported in animal models of amyotrophic lateral sclerosis (ALS) as well as in sporadic and genetic forms (SOD1 and C9orf72) of ALS. Post-mortem examinations and MRI scans in patients with ALS have found signs of iron accumulation in the central motor tract; and a high level of serum ferritin, which is a marker of iron levels, is associated with a lower prognosis. 

The high iron concentration of the brain, due to its high energy demand (high oxygen consumption), makes motor neurons particularly vulnerable to energy deficit and oxidative stress.

In ALS mouse models, the use of iron chelators has demonstrated neuroprotection and increased life expectancy, suggesting that elimination of excess iron from the brain can prevent neuronal loss and, consequently, a slow progression of the disease. Conservative chelation of iron refers to a modality whereby much of the iron that binds to the chelator is redistributed in the body rather than exhausted. Using a chelator, deferiprone, with this feature, in a safety pilot study, a very good safety profile was observed. Deferiprone eliminated excess iron from brain regions, reduced oxidative damage and cell death associated with regional iron deposits with no apparent negative impact on the iron levels needed. Now, the efficacy of this new therapeutic modality of neuroprotection is being evaluated in a randomized, double-blind, placebo-controlled, multicenter study.

Find out more on clinicaltrials.gov.

Edaravone was originally developed by Mitsubishi Tanabe Pharma Corporation to treat acute ischemic stroke, however it was then tested in people with MND. One theory about why motor neurones die in MND is that they are affected by oxidative stress. Edaravone acts as a ‘free radical scavenger’ helping to reduce the effects of oxidative stress (as explained in a post on our research blog).

The first Phase 3 clinical trial of edaravone in MND found no overall benefit in people with MND, but showed an improvement in breathing function in a subgroup of people with an early form of the disease. Two studies have been conducted in this subgroup of patients. Results of the second study, announced at the 27th International Symposium on ALS/MND in 2016, revealed that after 24-week intervention patients showed some signs of beneficial effect. It has been estimated that approximately 7% of people with MND were eligible to take part in the clinical trials, showing improvement in only a small amount of people.

In early May 2017, edaravone (Radicava) was approved to treat MND by the FDA (Food and Drug Administration), the drug licensing authority in the USA. Read more about edaravone on our blog.

Edaravone is currently available in Japan, South Korea, the U.S, Canada, Switzerland, and China. In 2018, Mitsubishi Tanabe Pharma applied for consideration of edaravone as a treatment with the European Medicines Agency.

The Phase 3 clinical trial testing an oral suspension formulation of edaravone (MT-1186) was launched in November 2019, but was paused in March 2020 due to the COVID-19 pandemic, it is currently ACTIVE, NOT RECRUITING. The study, recruiting up to 150 adults with ALS (ages 18 to 75 years), is taking place at 65 clinical sites in the U.S., Canada, Europe, and Japan (NCT04165824).

A Phase 3b study is estimated to begin in November 2020 and will aim to recruit 380 participants - Not yet recruiting (NCT04569084).

EH301 is a dietary supplement, combining pterostilbene and nicotinamide riboside, aiming to increase activity of sirtuins, proteins that are involved in multiple cellular processes known to go wrong in neurodegenerative disease and aging. 

In February 2019, a small Phase 1 trial reported results from 32 participants who were receiving 1,200mh of EH301 a day across four months. Most people taking EH301 significantly improved on ALSFRS-R, muscle strength, activity and mass, compared to people taking placebo, who were progressing at a 'normal rate'. Some adverse events were reported and 12 people withdrew from the study.

Phase 2 NO-ALS trial is now being prepared to replicate the findings in a larger group of people, recruiting in Norway. Find out more on clinicaltrials.gov.

GM604 is a regulator peptide that monitors and corrects the nervous system. Prior research revealed that, when administered intravenously, it has neuroprotective effects in people with MND diseases. Genervon, the company behind the drug GM604, have already shown through Phase 1 and Phase 2 clinical trials that the drug is safe in people living with MND and Parkinson’s disease. Read more on our website.

The Phase 2A trial, taking place in the USA, recruited 12 patients with ALS, out of which 8 received the active agent and 4 received placebo. Results of this study reported in Genervon’s research article showed that there was no difference in ALSFRS-R ratings between patients receiving GM604 and those receiving placebo. The research article was posted on the public publishing platform F1000 in March 2017 and is currently awaiting peer-review.

No information on FDA approval of GM604 for ALS has been released, with the last updated information on the FDA website dating back to 2015.

Find out more about this trial at clinicaltrials.gov

The HEALEY ALS Platform Trial is currently RECRUITING. It is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.

This platform trial aims to accelerate the process of drug development and the path for effective treatment for ALS/MND by testing multiple drugs simultaneously and adaptively. This design has been seen to be successful in cancer trials. Compared to traditional drug development, the platform trial is estimated to find an effective therapy more quickly (average 3.4 vs. 8.5 years), with fewer total participants (average 880 vs. 1400), and fewer participants on placebo (average 220 vs. 700).

Participants will have an equal chance to be randomized to all regimens that are active at the time of screening. Once randomized to a regimen, participants will be randomized in a 3:1 ratio to either study drug or placebo.

Currently three regimens active in the trial:

A – Zilucoplan (Phase 2)
B – Verdiperstat (Phase 3)
C – CNM-Au8

New regimens will be continuously added as new investigational products become available. The HEALEY ALS Platform Trial will enroll additional participants as each new regimen is available.

Read about Healey platform trial presentation from the 30th International Symposium on our research blog: Clinical trials part 1 – platform presentations: Highlights from Perth.

UPDATE - Jan 2021: Pridopidine added as fourth drug to platform trial.

Find out more information on clinicaltrials.gov.

Ibudilast, also known as MN-166, is an anti-inflammatory drug which is currently used to treat asthma, and tested for the treatment of MND and other neurodegenerative diseases (including Multiple Sclerosis) by Medicinova. It is thought to suppress inflammation, activate neuronal function and reduce the number of toxic glial (support) cells.

The Phase 2/3 trial is currently recruiting participants to evaluate the efficacy, safety and tolerability of MN-166 for 12 months followed by a 6-month open-label extension phase. Find out more on clinicaltrials.gov.

The Phase 2 randomised, placebo-controlled, double-blind clinical trial recruited 71 people with MND who were taking 60mg of ibudilast daily together with riluzole across 6 months, with a follow-up six month open-label phase. The treatment was shown to be safe and well-tolerated. Results of secondary outcome measures showed that, in some participants, the ALSFRS score didn’t decline. More detailed analyses revealed a connection between reduced disease progression while on ibudilast and higher survival rates after the treatment. Read on clinicaltrials.gov.

The Phase 1/2 biomarker study was completed in June 2020. This trialled a higher dose (100mg) in 35 participants taken across 36 weeks, while tracking their progression using an MND biomarker [11C]-PBR28. This marker is a protein that is abundant in toxic glial cells and can be traced using imaging. Effectiveness of using this marker to track progression after treatment with ibudilast is the primary objective. Secondary objectives include ALSFRS , muscle strength and slow vital capacity scores. Read on clinicaltrials.gov.

Masitinib inactivates a cellular enzyme called tyrosine kinase, which is believed to be involved in tissue inflammation. While inflammation of the central nervous system may not be a direct cause of MND, it is likely to play a role in the speed of disease progression. Reducing the activity of inflammatory cells in the brain may reduce the damage to motor neurones.

Phase 3 trial is now being planned by AB Science to test masitinib at two doses (4.5 and 6mg/kg/day) in combination with riluzole in 495 participants in Germany. The study should be completed in 2022. Find out more on clinicaltrails.gov.

Phase 2/3 trial of this clinical trial examined the safety and effectiveness of masitinib in combination with riluzole in 394 people with MND, when taken for nearly a year. AB Science, the company behind masitinib, has recently published promising results, showing improved ALSFRS-R score when given 4.5mg/kg of masitinib per day. However, no benefit on overall survival was observed. A further clinical trial that will aim to confirm the previously-found results is planned to run through 2017-2018.

In April 2018, AB Science announced that masitinib was given a negative opinion for marketing authorisation by the European Medicines Agency (EMA). 

This Phase 3 trial is currently RECRUITING participants in Australia.

An estimate of 30 participants will be randomised in a 1:1 ratio to receive MediCabilis CBD Oil or placebo oil. The treatment duration is 6 months with one-month safety follow up. Participants will be checked every month either face to face or via telephone and will be assessed to collect data for study objectives such as ALSFRS-R, Forced Vital Capacity, pain and spasticity score, and quality of life. Estimated Study Completion Date: January 2022

Read more about cannabis-based products for medicinal use on our research blog.

Find out more on clinicaltrials.gov.

Neuralstem is a stem cell treatment that involves several injections of foetal-derived neural stem cells into the spinal cord of patients.

The latest Phase 2 study involved giving injections into the lower regions of the spinal cord, at increasing doses (number of cells), to help work out the optimum number of stem cells to give (these injections are given as a surgical procedure). Results from this study confirmed that the transplantation can be safely performed at high doses, to both lumbar (lower back) and cervical (neck) regions.

It is unknown whether another Phase 2/3 study will be conducted in the future. 

NP001 is being developed by Neuraltus Pharmaceuticals Inc. It acts on particular cells within the immune system in the bloodstream, which in turn influences inflammation within the brain and spinal cord. The study is focusing on people with MND who are also showing signs of an elevated immune response. By ‘damping down’ the immune system, the aim is to reduce the inflammation which damages motor neurones.

Results from the initial Phase 2 study, reported in late 2012, suggested that the treatment was safe, but did not significantly slow the progression of MND. The trial recruited 136 participants in centres across USA and at one centre in Canada. 

In April 2018, Neuraltus Pharmaceuticals Inc. announced that results form their follow-up Phase 2 clinical trial that tested the treatment in 138 people with MND with evidence of increased inflammatory activity in the blood (C-reactive protein). The study didn’t show slower progression of the disease or improved breathing function.

Nuedexta is a drug that treats emotional lability (‘pseudo-bulbar affect’, or PBA) in MND and other neurological conditions. Emotional lability can be described as inappropriate emotional expression often characterised by uncontrollable laughing or crying; it is a feature of MND and some other neurological conditions.

Nuedexta was originally granted a marketing authorisation by the EMA in July 2013, but Avanir Pharmaceuticals Inc, the company who developed and manufacture the drug, did not take the further necessary steps to make it available in the UK, such as agreeing a price with the NHS under the Pharmaceutical Prices Regulation Scheme.

In February 2016, the European Medicines Agency (EMA) had withdrawn its marketing authorisation for Nuedexta in the EU.

The withdrawal has been made at the request of Avanir Pharmaceuticals Inc. Avanir have never made the drug available in Europe, and this decision means that it is not available to prescribe for patients in the EU. 

Because Nuedexta is a patented medicine, Avanir has the sole right to produce and distribute it; it will not be possible for another company to make it or for it to be imported into the EU – although it remains available in the USA

NurOwn (MSC-NTF cells) reprogrammes bone marrow-derived stem cells into neurone-supporting cells. These are then transplanted back to the same patient so that they can secrete neutrotrophic factors to protect and promote growth of neurones. This study is run by Brainstorm-Cell Therapeutics.

Brainstorm’s randomised, placebo-controlled Phase 2 trial of NurOwn in the USA looked at the safety and effectiveness of stem cell transplantation in 48 people. The injections were given into the spinal cord (intrathecally) and also into the muscle. Results announced in July 2016 revealed that NurOwn treatment was safe and well-tolerated. While not a primary objective of this trial phase, the study also showed beneficial effects of NurOwn as assessed by lower levels of inflammatory biomarkers in the cerebrospinal fluid (CSF).

Phase 3 trial has fully enrolled over 200 participants across centres in the USA to investigate NurOwn's effectiveness, and treatment is now underway so the trial is ACTIVE, not recruiting.

BrainStorm is expecting to have topline trial data by the end of 2020, which will potentially support the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration requesting approval.

Find out more about this trial at clinicaltrials.gov

PrimeC, developed by NeuroSense Therapeutics, is a combination treatment composed of ciproflaxacin and celecoxib, both existing medications. Ciprofloxacin is an antibiotic often used to treat bacterial infections, and celecoxib is a prescription non-steroidal anti-inflammatory agent, similar to aspirin and ibuprofen. Together these target two key features of ALS — inflammation of the nervous system and abnormal regulation of RNA activity — that contribute to motor neuron degeneration.

In pre-clinical studies in fish models, PrimeC showed outstanding results. Based on these results, NeuroSense filed a patent, and was granted an Orphan Drug Designation from the FDA and the EMA, for the use of PrimeC in ALS patients.

NeuroSense Therapeutics is currently running two clinical trials in ALS patients, in Israel and the USA.

The open-label Phase 2a clinical trial (NCT04165850) showed that PrimeC, given as a 303 mg capsule three times per day, was safe and well-tolerated in all 15 patients. The treatment slowed disease progression — as measured using the ALS Functional Rating Scale-Revised — and the decline in lung function throughout the final 3 months of a 6-month study period. Those results, however, did not reach statistical significance. This study will continue to investigate PrimeC in the enrolled patients for up to 15 months.

The ongoing Phase 1 trial (NCT04090684) taking place in the U.S., is designed similarly, but it expects to enroll 30 participants, who will be taking two capsules of PrimeC per day (instead of three).

Prosetin is an oral, brain penetrant, small molecule shown in multiple laboratory models of ALS to block MAP4K, a specific group of protein kinases that several leading academic researchers & drug companies have identified as a key player in ALS/MND.

While a Phase 1 clinical trial investigating Prosetin was due to start the summer of 2020, the COVID-19 pandemic delayed previously ongoing preclinical and clinical research. However, Project ALS’ goal is to initiate human clinical studies by the end of 2020.

In August 2020, the U.S. Food and Drug Administration has granted Prosetin orphan drug designation for the treatment of amyotrophic lateral sclerosis (ALS). While Prosetin’s orphan status will not change the timing or viability of clinical trials, it does make it eligible for research grants specific to orphan drugs. These could support more rapid and robust efforts to develop Prosetin as a clinically useful compound. It also allows Prosetin’s developers to seek additional FDA help and guidance when designing clinical trials.

A research paper detailing Prosetin’s development and mechanisms of action was published last year, in the journal Cell Chemical Biology.

Tirasemtiv is a muscle activator that increases force (contraction) and power of skeletal muscles and therefore delays muscle fatigue. Instead of aiming to slow down progression of MND, the aim of this drug treatment is to increase quality of life by increasing muscular strength. The drug is being developed by Cytokinetics.

A Phase 3 clinical trial (known as VITALITY-ALS) recruited 600 people with MND in the USA, Canada and Europe (including the UK). The trial tested the effectiveness of different doses of Tirasemtiv on breathing function over a period of 48 weeks. The trial was designed to try and reduce the side effects of the drug experienced in previous studies. In November 2017, Cytokinetics announced that tirasemtiv failed to meet its primary and secondary endpoints in their Phase 3 clinical trial. Read the press release here.

A new version of the drug, called Reldesemtiv, was tested in a Phase 2 trial (known as FORTITUDE-ALS) which recruited 458 people with MND worldwide. Treatment with oral reldesemtiv appears to slow the deterioration of function, including breathing capacity and muscle strength in people with MND – regardless of whether they are taking riluzole or edaravone.

Although Cytokinetics suspended the development of tirasemtiv, the results still support the potential of a new generation of fast skeletal muscle troponin activators, such as Cytokinetics‘ reldesemtiv, now in development, they conclude. In December 2019, Cytokinetics announced that the US Food and Drug Administration (FDA) has granted orphan drug status to reldesemtiv for the treatment of MND. Read an update from the 30th International Symposium on ALS/MND on our research blog.

Cytokinetics is currently preparing a global Phase 3 trial that will enroll more than 500 people with early MND, to test its investigational therapy reldesemtiv in slowing progressive muscle weakness. Cytokinetics announced details of the trial design, called COURAGE-ALS, which will build upon the results of the recently completed FORTITUDE-ALS Phase 2 trial at the 31st International Symposium (Dec 2020). The primary goal of COURAGE-ALS is to measure changes in the participants’ ALSFRS-R scores over the first 24 weeks.