Latest ALS Clinical Trial Information

ALS is the third most common neurodegenerative disease after Alzheimer’s and Parkinson’s diseases. The worldwide ALS prevalence is 4.42 per 1,00,000 people. (Xu et al., 2020) The onset of the disease is most common in people in their 40s to 70s, and 90% of cases occur without any family history of the disease. However, approximately 10% of these cases are familial ALS.

Once the disease develops, the patient gradually becomes immobile, has difficulty eating and speaking, and is unable to breathe. A ventilator can sustain life, but paralysis progresses throughout the body. The average life expectancy with a ventilator is 7 years. (Hayashi et al., 2020)

Unfortunately, there is no curative therapy; however, there are drugs that can delay the time to ventilator use by a few months. Only the motor nerves are affected (degenerated), and patients gradually lose the ability to move their bodies while remaining conscious. The disease is also characterized by a very heavy burden of nursing care, as the patient requires around-the-clock care.

There are several ongoing studies worldwide to achieve a fundamental cure.

This website provides the latest information on ALS clinical trials, based on scientific evidence.

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Daisuke Ito M.D. Ph.D.
Specially Appointed Professor
Department of Physiology/Memory center
Keio University School of Medicine
35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan
https://keio-memory-clinic.com

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Kensuke Okada

#The following are the criteria for clinical trials to be considered:

1) There is a reliable preclinical study

2) Phase II or higher in principle

3) High social and medical importance Last update　June 17, 2022

• Qalsody, Tofersen

Action: Antisense oligonucleotide (ASO) against superoxide dismutase 1 (SOD1) suppresses SOD1 expression.

The subjects are patients with familial ALS with SOD1 mutations*.　

Previous study results: No change was observed for the primary endpoint of ALSFRS-R (rate of symptom progression) in the double-blind period at six months (p=0.97).

Future extension studies hope to show the effect of the drug on slowing the rate of progression in the initial active drug group compared to that in the initial placebo group.

Details

Clinical trial results: Phase III: There was no positive effect on the primary efficacy endpoint of change from baseline in ALSFRS-R total score at 28 weeks (double-blind period) in the primary analysis group (rapid progressive group) (placebo n=21; active n=39) (between-group difference 1.2; p=0.97). Serious neurologic adverse events (myelitis, meningitis, lumbar disc disease, intracranial hypertension, and papilledema) occurred in approximately 7% of patients with active drug. Zero occurred in the placebo group.(Miller et al., 2022)

However, a trend in favor of Tofelsen was observed for the secondary and exploratory endpoints (motor function, respiratory function, and quality of life) (Miller et al., 2021).

Tofelsen treatment significantly decreased the CSF neurofilament light chain (NLF) level, indicative of neuronal damage [60% reduction in active group and 20% increase in placebo group in the rapidly progressive group].

In an open-label extension study (after 12 months), ALSFR was 3.5 points (95% [CI]:0.4-6.7) and lung capacity (vital capacity) was 9.2% (95% CI:1.7-16.6) higher in the initial active drug group compared to that in the initial placebo group.

ClinicalTrials.gov Identifier: NCT03070119

Dosage: Monthly intrathecal injection

Side effects: In addition to adverse events related to lumbar puncture (headache, back pain, etc.), serious neurological events, including myelitis, occurred in the Tofelsen group.

Clinical Trials Status: On July 26, 2022, the FDA agreed to review a new drug application for tofersen. The application is based on a Phase 3 study that showed a greater reduction in neurofilament light chain NfL levels (a marker of transcellular damage) in the actual drug group. On 22 March 2002, the Advisory Committee stated that the reduction in neurofilaments was likely to indicate a clinical benefit for tofersen. However, the Committee voted that the data to date did not provide substantial evidence to support approval. However, the FDA granted accelerated approval (25 April 2023) on the basis that the reduction in neurofilaments was likely to provide a clinical benefit. For accelerated approval, efficacy must be demonstrated in subsequent studies.

A Phase III ATLAS clinical trial was initiated to test whether starting Tofelsen treatment in pre-onset individuals with SOD1 gene mutations can delay the onset of clinical symptoms.

ClinicalTrials.gov Identifier: NCT04856982　

Participants are being recruited.

Expected completion: August 2027

Remarks: Carriers with familial ALS who have a rapidly progressive SOD1 mutation, but are not yet symptomatic, are eligible.

In more than 90% of ALS cases, a protein called TDP-43 accumulates abnormally in the neurons in the brain and spinal cord.

However, patients with ALS with SOD1 mutation, the most common familial form of ALS, do not have accumulation of TDP-43, instead have abnormal accumulation of SOD1. These accumulated proteins are the key causes of the disease.

Treatment

Currently, only two drugs have been approved in the USA and Japan, both of which slow disease progression, but have limited efficacy. Unfortunately, there are no drugs that can fundamentally cure this disease.

Riluzole (Rilutek®)

Edaravone (Radicat®)

(For details, please refer to the glossary)

Riluzole (Rilutek®) Oral Riluzole

Action: It exerts a protective effect on nerve cells by suppressing nerve over-excitation

Clinical trial results: The results of previous double-blind studies (n=1477 patients) show that it prolongs survival by 2–3 months.

Side effects: The most common side effects are gastrointestinal symptoms, such as nausea, vomiting, diarrhea, anorexia, drowsiness, asthenia, and dizziness.

Laboratory results have reported liver dysfunction and anemia.

Details

Action: A drug that suppresses glutamate-induced excitotoxicity and exerts a protective effect on nerve cells. However, there is little evidence of its efficacy in rodent mouse models (Hogg et al., 2018).

Clinical trial results: prolonged survival (time to death or tracheostomy) by 2–3 months based on a meta-analysis of four double-blind controlled trials (n=1477 patients). (Miller et al., 2012)

However, patients with a forced vital capacity (%FVC) <60% are not expected to benefit.

Dosage: One tablet twice daily (before breakfast and dinner); a daily dose of 100 mg riluzole should be administered orally. The reason for pre-meal administration is that the absorption rate of the drug is lower after a high-fat meal than in an empty stomach.

Remarks: This was the most scientifically proven treatment. This is the only drug approved in Japan, the U.S., and Europe.

Edaravone (Radicat®) intravenous infusion Edaravone

Action: Removal of reactive oxygen species

Results: In patients with mild disease within 2 years of onset, 6 months of treatment reduced further decline (speed of progression) in the revised ALS Functional Rating Scale (ALSFRS-R*) by 2.49 points. However, no benefit was observed in patients with a disease duration of less than 3 years.

Long-term observation in Germany (approximately 1 year) showed no effect on ALSFRS-R reduction (speed of symptom progression) or survival (time to death or tracheotomy) under riluzole treatment.

Current status: Phase III study of oral medication (once daily) is ongoing.

Remarks: On December 10, 2021, edaravone oral suspensions (drinkable) were reported to be generally consistent with the safety profile of intravenous formulations. The U.S. Food and Drug Administration (FDA) approved RADICAVA ORS® (edaravone oral suspension) for treating ALS (May 12, 2022).

Details

Action: Removal of reactive oxygen species. There is evidence of its efficacy in rodent models (Ito et al., 2008).

In subjects with ALS severity classification*1 or 2, with a forced vital capacity of ≥80% and with < 2 years of disease duration (68 active and 66 placebo), the difference between groups after six courses of treatment (6 months) was statistically significant [Functional Rating Scale (ALSFRS-R) of 2.49 points (0.99, 3.98, p=0.0013)]. (Writing-Group-Edaravone-ALS-Study-Group, 2017)

However, no significant difference was found in the clinical trial (100 active and 99 placebo), which included patients with a disease duration of 2–3 years. (Abe et al., 2014)

In a German multicenter, propensity score-matched, long-term cohort study, with 130 patients in the active drug (edaravone + riluzole group) (median observation time 12.7 months) and 133 patients in the placebo drug (edaravone alone group) (11.1 months), the rate of ALSFRS-R decline (disease progression) or survival (time to death or tracheotomy) did not show any improvement under riluzole treatment (Witzel et al., 2022)

However, a similar analysis in the U.S., with 318 patients treated with the active drug and 318 patients treated with the placebo drug, with 65.4% of both groups treated with riluzole, showed that edaravone prolonged life by 6 months (Mitsubishi Tanabe Pharma America, Inc., 2022).

Dosage: Two sachets (total 60 mg edaravone) were administered via intravenous infusion once daily for 60 min. Usually, a 28-day course consisting of an administration phase and withdrawal phase was repeated. The first course of treatment was administered daily for 14 days. The second and subsequent courses consisted of 10 days of administration followed by a 14-day rest period.

Side effects: Renal impairment (0.3% or less) and hepatic dysfunction (0.24%)

Remarks: Not approved in Europe because there is no evidence of reduced progression or prolonged survival after more than 1 year of treatment.

On December 10, 2021, edaravone oral suspensions (drinkable) administered every 2 weeks were reported to be generally consistent with the safety profile of the intravenous formulation. The U.S. Food and Drug Administration (FDA) approved RADICAVA ORS® (edaravone oral suspension) for treating ALS (May 12, 2022).

Clinical Trial Status: Global Phase III Study to Evaluate the Long-Term Safety and Tolerability of Edaravone Oral Suspension (MT-1186) in ALS　

ClinicalTrials.gov Identifier: NCT05151471

Recruitment Completed

Expected completion: June 2024　

Remarks: This was a global study to confirm the efficacy of edaravone administration once daily. The change from intravenous to oral edaravone makes it less invasive and allows daily administration.  

 AVP-923 Nuedexta, Zenvia

Action a fixed-dose combination of two approved drugs, dextromethorphan, and quinidine.

Dextromethorphan: cough syrup, a weak antagonist of NMDA receptors and agonist of sigma 1 receptors, molecular chaperones located in membranes of the endoplasmic reticulum

Quinidine: a drug for arrhythmia. Quinidine increases the bioavailability of dextromethorphan.

Clinical Trial Status: Pseudobulbar affect (involuntary episodes of crying or laughing)-episode daily rate was ~50% for more active than for placebo. (Pioro et al., 2010)

Side effects: diarrhea, dizziness, cough, vomiting, weakness, and swelling of the feet and ankles.

Note: In October 2010, Nuedexta was approved by the U.S. FDA to improve pseudobulbar effects in ALS and multiple sclerosis.

Relyvrio AMX0035 combination of sodium phenylbutyrate 3g and tauroursodeoxycholic acid (taurursodiol) 1g

Action: To relieve disorders caused by abnormal protein accumulation.

Results: The ALSFRS-R (rate of progression) decreased by 2.52 points after 24 weeks of treatment; median survival increased by 6.5 months.

Side effects: gastrointestinal symptoms

Details

Action: Sodium phenylbutyrate and tauroursodeoxycholic acid reduce endoplasmic reticulum stress. Tauroursodeoxycholic acid improves mitochondrial damage.

Clinical Trial Results: In a phase II trial, patients with ALS (137 patients) with an onset of less than 18 months had a significantly reduced ALSFRS-R rate (difference of 0.42 points/month) in the active drug group over a 24-week observation period. The risk of death was reduced by 44% (HR, 0.56; 95% CI, 0.34–0.92).

The median survival was 25.0 months in the active drug start group and 18.5 months in the placebo start group, an increase of 6.5 months. (Paganoni et al., 2020)

In the open-label continuation study, the initial active drug group showed a 49% reduction in the risk of serious illnesses (death + tracheostomy/ventilator use) and a 44% reduction in the risk of hospitalization (Paganoni et al., 2022).

Side effects: Gastrointestinal events occurred more frequently (>2%) and AMX0035 was discontinued more frequently than the regimen in the placebo group.

Dosage: once daily for the first 3 weeks, twice daily thereafter

Current status of the clinical trial: The U.S. Food and Drug Administration (FDA) has approved Relyvrio for the treatment of adults with ALS on Phase 2 Data. (September 29, 2022) . If the ongoing Phase 3 trial shows no efficacy, this drug must be withdrawn. Amylyx announced that it has priced Relyvrio at approximately $158,000 per year, which is below Radicava’s price.

 Note: Marketed as sodium phenylbutyrate for urea cycle disorders (Buphenyl®).

Ursodeoxycholic acid (Urso®) is widely prescribed to improve liver function in patients with chronic liver diseases. Tauroursodeoxycholic acid (TUDCA) is an ursodeoxycholic acid conjugated with taurine, and is sold as a supplement.

Masitinib

Action: Exerts neuroprotective effects by reducing inflammation

Past trial results: 48 weeks of treatment in combination with riluzole in patients with a relatively slow decline of ALSFRS-R by 3.4 points.

Prolonged survival by 25 months and reduced risk of death by 47% in mild patients with slow progression after an average of 75 months of observation.

Side effects: skin rash, nausea, respiratory failure, liver damage

Clinical Trial Status: Phase III　

Details

Action: Inhibitor of type III growth factor receptor family tyrosine kinases, including PDGF-R, c-Kit, FLT3, and CSF-1R. Thought to act on mast and microglial cells to reduce inflammation and provide neuroprotection; prolonged survival of SOD1G93A rats by 40% (Trias et al., 2016)

Clinical trial results: In phase II/III. 3.4 point in ALSFRS-R suppression (p= 0.016) was difference between masitinib and placebo (99 actives, 102placeboes) combined with riluzole for 48 weeks in patients whose ALSFRS-R decline rate was less than 1.1 points/month (Mora et al., 2020), and the active drug also suppressed the FVC% by 7.5 points (p= 0.03) in active group.

However, there was no significant difference in the analysis of all patients, including those with the rapidly progressive form.

In the long-term survival analysis, masitinib significantly extended survival by 25 months (P = 0.037) and reduced the risk of death by 47% (P = 0.02) in patients with ALSFRS-R declining at a rate of 1.1 points/month or less and all ALSFRS-R scores ≥2 points (130 patients on active and 133 on placebo) after an average follow-up of 75 months. (P = 0.025). However, the analysis of all patients showed no significant differences (P = 0.196). (Mora et al., 2021)

Side effects: Serious side effects: 31% (e.g., liver damage) (18% placebo)

Clinical Trials Status: prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group study (phase III) to compare the efficacy and safety of masitinib combined with riluzole versus placebo combined with riluzole

ClinicalTrials.gov Identifier: NCT03127267　

Recruiting participants

Expected completion: December 2022

Remarks: Unlike the pharmacological effects of previously approved drugs, this drug targets inflammation.

Health Canada has initiated a review of masitinib’s application for approval, which is expected to be completed within 200 days (~Dec, 2022).

This drug has been used to treat mast cell tumors, a malignant tumor in dogs and cats. Launched in Europe as Masivet in 2008.

Relyvrio AMX0035 combination of sodium phenylbutyrate 3g and tauroursodeoxycholic acid (taurursodiol) 1g

Action: To relieve disorders caused by abnormal protein accumulation.
Results: The ALSFRS-R (rate of progression) decreased by 2.52 points after 24 weeks of treatment; median survival increased by 6.5 months.
Side effects: gastrointestinal symptoms
Details
Action: Sodium phenylbutyrate and tauroursodeoxycholic acid reduce endoplasmic reticulum stress. Tauroursodeoxycholic acid improves mitochondrial damage.
Clinical Trial Results: In a phase II trial CENTAUR (NCT03127514), patients with ALS (137 patients) with an onset of less than 18 months had a significantly reduced ALSFRS-R rate (difference of 0.42 points/month) in the active drug group over a 24-week observation period. The risk of death was reduced by 44% (HR, 0.56; 95% CI, 0.34–0.92).
The median survival was 25.0 months in the active drug start group and 18.5 months in the placebo start group, an increase of 6.5 months. (Paganoni et al., 2020)
In the open-label continuation study, the initial active drug group showed a 49% reduction in the risk of serious illnesses (death + tracheostomy/ventilator use) and a 44% reduction in the risk of hospitalization (Paganoni et al., 2022).
Side effects: Gastrointestinal events occurred more frequently (>2%) and AMX0035 was discontinued more frequently than the regimen in the placebo group.
Dosage: once daily for the first 3 weeks, twice daily thereafter
Current status of the clinical trial: The U.S. Food and Drug Administration (FDA) has approved Relyvrio for the treatment of adults with ALS. (September 29, 2022) . Amylyx announced that it has priced Relyvrio at approximately $158,000 per year、which is below Radicava’s price.
Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment (Phoenix): to confirm results from Phase II study in a larger group of (600) ALS patients.
Primary Outcome: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
69 sites in the U.S. and Europe
ClinicalTrials.gov Identifier: NCT05021536
Enrollment complete, Expected to conclude in 2024
Note: Marketed as sodium phenylbutyrate for urea cycle disorders (Buphenyl®).
Ursodeoxycholic acid (Urso®) is widely prescribed to improve liver function in patients with chronic liver diseases. Tauroursodeoxycholic acid (TUDCA) is an ursodeoxycholic acid conjugated with taurine, and is sold as a supplement.

EPI-589, (R)-troloxamide quinone

Action: Antioxidant. EPI-589 was possibly more potent than edaravon in ALS cell models.
Clinical Trial Status: Exploratory study of EPI-589 in amyotrophic lateral sclerosis, phase IIa was completed. EPI-589 was safe and well tolerated.
ClinicalTrials.gov Identifier: NCT02460679,
Dosage: Oral administration, a dose of 500 mg twice per day at least an hour before eating for 3 months
The EPIC-ALS trial (phase II, jRCT2061210031):
10 participants
Primary Outcome: ALSFRS-R after six months of treatment. Cannot be combined with edaravone.
Recruitment Status: Active, not recruiting
Expected completion: October 2023

SLS-005 (Trehalose)
Action: Activates autophagy and promote the clearance of toxic protein accumulation.
Clinical Trial Status: Phase II/III
Primary Outcome ALSFRS-R
Dosage: weekly intravenous infusion for 6 months
ClinicalTrials.gov Identifier: NCT05136885
Enrollment complete
Expected completion: October 2023

Reldesemtiv

Action: Increases muscle contractility

Past Clinical Results: In a phase II trial, Reldesemtiv tended to slow the decline in lung function and ALSFRS in ALS patients; however, this was not significant.

Clinical Trial status: COURAGE-ALS Phase III

Details

Action: a fast skeletal muscle troponin activator . It slows the rate of calcium release from regulatory troponin complexes in skeletal muscle fibers and increases skeletal muscle contractility by sensitizing sarcomeres to calcium.

Previous Trial Results: In a phase II clinical trial (NCT03160898), Reldesemtiv tended to slow the decline in vital capacity and ALSFRS-R in patients with ALS compared to placebo; however, this was not significant.

Current Status of Clinical Trials: In a Phase III study of the COURAGE-ALS test (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints-in ALS), the selection criteria were cases with onset within 2 years and moderate to rapid progression. In June 2022, a long-term open-label extension study (OLE) was initiated.

Dosage: oral, twice daily

ClinicalTrials.gov Identifier: NCT04944784

Clinical trial results: On March 31, 2023, the Phase 3 Clinical Trial of Reldesemtiv was discontinued after Data Monitoring Committee found no effect on primary endpoints.

Verdiperstat

Action: Inhibits reactive oxygen species and reduces inflammation by inhibiting myeloperoxidase.

Current Status: Phase II/III. The drug did not show efficacy in the prespecified primary outcome, disease progression, as measured by ALS Functional Rating Scale-Revised (ALSFRS-R), and survival.

ClinicalTrials.gov Identifier: NCT04436510

Entry Completed

Expected completion: November 2022

Pridopidine, ACR16, TV-7820, Huntexil, ASP2314

Mode of action: Reduces endoplasmic reticulum stress* via the sigma 1 receptor

Administration: Oral administration

Clinical Trial Status: Phase II/III

ClinicalTrials.gov Identifier: NCT04615923

End of entry

Expected completion: 2022

Mecobalamin

Action: vitamin B₁₂

Results: In patients with ALS less than one year after onset, the active drug reduced the ALSFRS-R total score by approximately 43% (Oki et al., 2022).

Dosage: Intramuscular injection twice a week

Details

Action: Active form of vitamin B₁₂, widely administered for the treatment of peripheral neuropathy and megaloblastic anemia. Lowers levels of neurotoxic homocysteine, decreases levels of reactive oxygen species, and inhibits glutamate neurotoxicity.

Clinical Trial Results: Phase III Study of High-Dose E0302 in Amyotrophic Lateral Sclerosis – Physician-Initiated Clinical Trial　

ClinicalTrials.gov Identifier: NCT03548311

Subjects: A total of 130 patients less than 1 year after onset, ALS severity classification grade 1 or 2, and a 1- or 2-point decrease in the total ALSFRS-R score (moderate progression) over the observation period (12 weeks). After 16 weeks of treatment, the active drug was effective in reducing the ALSFRS-R total score by approximately 43% (difference of 1.97). Approximately 90% of the subjects received riluzole. Combination therapy with riluzole and high-dose methylcobalamin resulted in significantly lesser symptom progression than riluzole monotherapy. Adverse events did not differ from those of placebo. (Oki et al., 2022)

Dosage: Intramuscular injection of 50 mg twice weekly (50–100 times the approved dose for peripheral neuropathy)

Note: The Pharmaceutical Affairs and Food Sanitation Council physician in Japan designated this drug as Orphan Drug# (April 28, 2022)

#Drugs for which special support measures are provided to promote the testing and research and medical devices for which the number of patients is small despite their high medical necessity.

SAR443820 (DNL788)

Action: Receptor-interacting protein kinase 1 (RIPK1) inhibitor

It inhibits inflammation and neuronal cell death (necroptosis).

Clinical trial status: Phase II trial started (HIMALAYA trial)

NCT05237284

Recruiting

Scheduled to end in April 2025

OBP-601 (Censavudine, TPN-101)

Action: Reverse transcriptase inhibitor. It was originally developed for treating human immunodeficiency virus infection. This drug is expected to suppress inflammation and protect cells by inhibiting the reactivation of retrotransposons.

Current status of clinical trial: Phase 2a study in 40 patients with ALS and/or FTD with Hexanucleotide Repeat Expansion in the C9orf72 Gene.

Dosing regimen: Once daily, orally

Details

Action: Reverse transcriptase inhibitor. Originally developed as a treatment for human immunodeficiency virus infection. ALS and frontotemporal dementia are thought to involve replication of retrotransposons with reverse transcriptase, causing random translocations and mutations within genome. This possibly lead antiviral immune responses, neuroinflammation, and eventually cell death. (Liu et al., 2019) This drug inhibits reverse transcriptase, suppresses neuroinflammation, and protects neurodegeneration.

Current status of the trial: phase 2a study of 40 patients with ALS or FTD in C9ORF72, 6 months double-blind followed by 6 months open-label treatment. Primary endpoints were safety and tolerability; secondary endpoints were pharmacokinetics, CSF and blood neurofilament light chain, and ALS Functional Rating Scale-revised.

ClinicalTrials.gov Identifier: NCT04993755

Participants are being recruited. 

Expected completion: September 2023 Remarks: Unlike previous drugs, targeting retrotransposons is novel.

Sotuletinib BLZ945,

Action: CSF-1R inhibitor. Suppresses microglial activity and excessive inflammation.

Current Status: Phase II open-label study in 49 ALS patients. The primary endpoint is the PET signal of [11C]PBR28, which binds to Translocator protein (TSPO) and is an indicator of microglial activation.

Dosing regimen: oral administration.

ClinicalTrials.gov Identifier: NCT04066244

Recruiting

Expected completion: 2024

Macrophage-Targeted Sodium Chlorite (NP001)

Action: NP001 is a proprietary formulation of sodium chlorite and is a regulator of innate immune function (macrophage activation regulator).

Dosing regimen: Infusion

ClinicalTrials.gov Identifier: NCT0128163, NCT01281631

Criteria for selection: Onset of symptoms less than 3 years prior to study entry. Forced Vital Capacity (FVC) at least 70% of that predicted for age and height.

Phase 2 Completed

Results: In the C-reactive protein (CRP) > 1.13 mg/L group (high inflamation), the NP001-treated arm lost 1.5 points of the ALSFRS-R score over six months, whereas the placebos lost 4.4points (p = 0.03). In the CRP < 1.13 mg/L group, there was no difference in the clinical outcome  (Zhang et al., 2022). NP001 decrease in plasma biomarkers (LPS-binding protein, hepatocyte growth factor, lipopolysaccharide, IL-18, soluble CD163).

Autologous bone marrow mesenchymal stem cell therapy

Action: Cell therapy in which mesenchymal stem cells harvested from bone marrow fluid. Stem cells are expected to protect neurons and suppress neuro-inflammation.

Clinical trial status: Double-blind, randomized, controlled trial of intravenous administration of autologous bone marrow mesenchymal stem cells in patients with amyotrophic lateral sclerosis (ALS).

jRCT2013190010

Key Selection Criteria: ALS severity classification 1–3 within 3 years of onset.

Administration: Autologous mesenchymal stem cells harvested from bone marrow fluid, cultured and expanded in vitro, and administered intravenously to patients.

Participants wanted: Available in Japan (Sapporo Medical University Hospital)

Scheduled completion: July 2024

NurOwn® (Autologous bone marrow-derived neurotrophic factor-secreting mesenchymal stromal cells)

Action: A cell therapy in which autologous bone marrow mesenchymal stem cells harvested from bone marrow are cultured and grown ex vivo and administered intrathecally to patients.

Current Status of Clinical Trials: A phase III trial failed to demonstrate efficacy on the primary endpoint in all patient groups. However, subgroup analysis showed statistically significant efficacy in the patient group with an ALSFRS-R of at 27-35 points at baseline.

Details

Action: A cell therapy in which autologous bone marrow mesenchymal stem cells harvested from the patient’s bone marrow are cultured and expanded ex vivo and administered intrathecally. The cells produce neurotrophic factors and are expected to have neuroprotective effects.

Dosing: Three bi-monthly intrathecal injections

The preceding phase III trial of BrainStorm’s NurOwn cells, an autologous mesenchymal stem cell transplant, failed to demonstrate efficacy. (Percentage of ALSFRS-R change showing improvement of 1.25 points/month or more before and after treatment: 32.6% in the NurOwn group and 27.7% in the placebo group; no statistically significant difference) (Cudkowicz et al., 2022).

However, after correction of the statistical methods, the subgroup analysis showed that the subgroups of patients with ALSFRS-R of 27-35 points at baseline had significantly lower ALSFRS-R decline in Erratum.

（https://onlinelibrary.wiley.com/doi/epdf/10.1002/mus.27472） ClinicalTrials.gov Identifier: NCT03280056

Pegcetacoplan (EMPAVELI™)

Action: Inhibition of complement, which is involved in inflammation. It was used to treat adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

Clinical Trial Status: Phase II

Participants are being recruited.

Details

Action: Inhibition of C3 complement, which is involved in inflammation of the motor endplates at the nerve junction. It is used to treat adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Animal studies have been inconclusive regarding the efficacy of complement inhibition. (Lobsiger et al., 2013; Woodruff et al., 2008)

Clinical trial status: Evaluation of the efficacy and safety of Pegcetacoplan (pegetacoplan) in adult patients Phase II

ClinicalTrials.gov Identifier: NCT04579666 not recruiting

not recruiting

Criteria for selection: Sporadic ALS with onset within 16.5 months (72 weeks) and slow vital capacity >60% of the predicted value

Dosage: Subcutaneous injection twice a week

Side effects: Streptococcus pneumoniae, meningococcus, and Haemophilus influenzae type B (vaccination required)

Note: Labulizumab (Yurtomiris®), an inhibitor of the C5 complement, was discontinued early after an interim analysis of a phase III trial, because it failed to demonstrate efficacy.

Recombinant human HGF protein

Action: Neurotrophic factor. It inhibits progression in rodent models (Ishigaki et al., 2007)

Clinical trial status: A phase II trial consisting of a placebo-controlled double-blind and open-label continuation study to evaluate the efficacy and safety of 6-month intraspinal administration of HGF protein (KP-100IT) using NP022 (intrathecal catheter and subcutaneous implant port). ALS severity of 1 or %FVC ≥70% within 30 months of onset

UMIN Study ID: UMIN000022050

End of entry: The observation date for the last case was completed.

AT-1501 (anti-CD40L) (Tegoprubar)

Action: Suppresses neuroinflammation

Clinical Trial Status: Phase IIa suppressed disease progression compared to that in the controls in the ALS clinical trial data.

Details

Action: Suppresses neuroinflammation by inhibiting the interaction between CD40 ligand (CD40L), a surface antigen of immune cells, and CD40 receptors.

Clinical trial status: Phase IIa completed

Tegoprubart well tolerated, no serious adverse events.

ALSFRS decline was suppressed compared to that in the controls in an ALS clinical trial data set in the ALS PRO-ACT database*.

Dosage: Biweekly intravenous administration

Latozinemab, AL001, GSK4527223

Action: Recombinant human anti-sortilin monoclonal IgG1.

Sortilin is a sorting receptor for intracellular trafficking. It is involved in neurotrophic factors, signal transduction, and lysosomal degradation. It regulates the endocytosis and degradation of progranulin, a major cause of frontotemporal dementia. Progranulin levels are reduced by 50%-70% in this disease. Suppression of sortilin with this drug increases progranulin. 

Clinical Trial Status: Phase 2 for ALS due to C9ORF72 mutation

The primary endpoints are safety, tolerability, pharmacokinetics and pharmacodynamics; plasma and CSF progranulin levels

ClinicalTrials.gov Identifier: NCT04436510

not recruiting

Low-dose aldesleukin

Action:Low dose (ld) IL2 boosted peripheral regulatory T cells (Tregs) and modified inflammation.

Clinical Trial Status: Phase II, completed

ClinicalTrials.gov Identifier: NCT02059759

Criteria for selection: ALS disease duration 24 months, VC 70%, not previously treated with riluzole.

Dosage: Subcutaneous injection in 5-day cycles every 28 days

Results: The primary efficacy outcome was time to death (survival) at 21 months (640 days) post-randomization. Aldesleukin tended to improve survival rates by 19% compared with a placebo, but the findings failed to reach statistical significance. In patients with lower levels of CSF phosphorylated neurofilament heavy chain (biomarker of disease severity), Aldesleukin results in a significant reduction – by 43% – in the risk of death and also slower disease progression in ALSFRS-R scores.

Ropinirole (Requip®) Ropinirole

Action: A drug discovered through research on ALS patient-derived iPS cells. Originally, it was widely administered as a treatment for Parkinson’s disease.

Clinical trial results: It reduced ALSFRS-R during phase I/II in the double-blind period; however, the difference was not statistically significant.

Details

Action: The drug was discovered by high-throughput screening of ALS patient-derived iPS cells. Originally, this drug was a dopamine agonist and was widely administered to patients with Parkinson’s disease. It ameliorates mitochondrial dysfunction by inhibiting the accumulation of abnormal TDP-43 and FUS proteins. However, this is not effective for ALS-iPS with SOD1 mutations.

Previous results: Phase I/III: 13 patients on the active drug and 7 patients on the placebo drug.

ALSFRS-R showed a 5.9±4.1 points decline in the ropinirole group and a 15.6±8.8 decline in the placebo group during the double-blind period (6 months); however, this was not statistically significant. (Morimoto et al., 2022)

Dosage: Oral administration

Side effects: gastrointestinal symptoms, drowsiness, leg edema

Bosutinib (Bosulif®) Bosutinib

Action: A drug discovered in the study of ALS patient-derived iPS cells. Originally this drug was used for chronic myeloid leukemia.

Clinical trial results: In 5 among 9 patients, the decline in ALSFRS-R stopped after 12 weeks of phase I treatment.

Current status: Phase II trial started. No recruitment.

Details

Action: Induces the removal of abnormally accumulated proteins via autophagy. This drug was discovered through research on ALS-patient-derived iPS cells. This drug is effective for ALS patients with SOD1 mutations.

Past clinical trial results: In phase I, three of nine patients with ALS discontinued treatment due to adverse events (Diarrhea, liver dysfunction).

After 12 weeks of treatment, in 5 among 9 patients, the decline (progressing) in the ALSFRS-R scores stopped. Patients with suppressed ALSFRS-R decline had low blood neurofilament L (a marker of neuropathy) at baseline.(Keiko Imamura et al., 2022)

Current status: Phase II open-label multicenter trial has started in Japan; the data will be compared with external data from previous ALS clinical trials and JaCALS*. Target number of patients: 25

No recruitment

Dosage: Oral administration

Side effects: diarrhea, liver dysfunction, etc. 

• Qalsody, Tofersen

Action: Antisense oligonucleotide (ASO) against superoxide dismutase 1 (SOD1) suppresses SOD1 expression.

The subjects are patients with familial ALS with SOD1 mutations*.　

Previous study results: No change was observed for the primary endpoint of ALSFRS-R (rate of symptom progression) in the double-blind period at six months (p=0.97).

Future extension studies hope to show the effect of the drug on slowing the rate of progression in the initial active drug group compared to that in the initial placebo group.

Details

Clinical trial results: Phase III: There was no positive effect on the primary efficacy endpoint of change from baseline in ALSFRS-R total score at 28 weeks (double-blind period) in the primary analysis group (rapid progressive group) (placebo n=21; active n=39) (between-group difference 1.2; p=0.97). Serious neurologic adverse events (myelitis, meningitis, lumbar disc disease, intracranial hypertension, and papilledema) occurred in approximately 7% of patients with active drug. Zero occurred in the placebo group.(Miller et al., 2022)

However, a trend in favor of Tofelsen was observed for the secondary and exploratory endpoints (motor function, respiratory function, and quality of life) (Miller et al., 2021).

Tofelsen treatment significantly decreased the CSF neurofilament light chain (NLF) level, indicative of neuronal damage [60% reduction in active group and 20% increase in placebo group in the rapidly progressive group].

In an open-label extension study (after 12 months), ALSFR was 3.5 points (95% [CI]:0.4-6.7) and lung capacity (vital capacity) was 9.2% (95% CI:1.7-16.6) higher in the initial active drug group compared to that in the initial placebo group.

ClinicalTrials.gov Identifier: NCT03070119

Dosage: Monthly intrathecal injection

Side effects: In addition to adverse events related to lumbar puncture (headache, back pain, etc.), serious neurological events, including myelitis, occurred in the Tofelsen group.

Clinical Trials Status: On July 26, 2022, the FDA agreed to review a new drug application for tofersen. The application is based on a Phase 3 study that showed a greater reduction in neurofilament light chain NfL levels (a marker of transcellular damage) in the actual drug group. On 22 March 2002, the Advisory Committee stated that the reduction in neurofilaments was likely to indicate a clinical benefit for tofersen. However, the Committee voted that the data to date did not provide substantial evidence to support approval. However, the FDA granted accelerated approval (25 April 2023) on the basis that the reduction in neurofilaments was likely to provide a clinical benefit. For accelerated approval, efficacy must be demonstrated in subsequent studies.

A Phase III ATLAS clinical trial was initiated to test whether starting Tofelsen treatment in pre-onset individuals with SOD1 gene mutations can delay the onset of clinical symptoms.

ClinicalTrials.gov Identifier: NCT04856982　

Participants are being recruited.

Expected completion: August 2027

Remarks: Carriers with familial ALS who have a rapidly progressive SOD1 mutation, but are not yet symptomatic, are eligible.

Adeno-associated virus rh10 containing an anti-SOD1 microRNA (AAV-miR-SOD1)

Action: Adeno-associated virus rh10 containing an anti-SOD1 microRNA suppresses SOD1 expression by introducing a microRNA against SOD1 in the cerebrospinal fluid.

Results of previous studies: One case report: A rapidly progressive case of SOD1 mutation A5V* was treated (Mueller et al., 2020).

The patient required steroid therapy for AAV-associated meningitis. The patient died of respiratory failure 15.6 months after treatment and 20 months after onset.

Dosage: One intrathecal injection.

The treatment resulted in a 90% decrease in spinal SOD1 protein levels; however, it did not improve life expectancy.

Remarks: One case of non-rapidly progressive form (D91A-D91A mutation) was treated; however, the clinical course is not yet available.

ION363, Jacifusen

Action: Suppresses FUS expression by ASO. FUS is the third most common gene in familial ALS.

Clinical trial results: One case report; patient with FUS mutation P525L# (25 years old).

The patient had already experienced respiratory failure at the start of the treatment and was administered NTTV*. After starting treatment, ALSFRS seemed to decrease slowly, but respiratory failure and dysphagia progressed, and the patient died from complications approximately 1 year after starting treatment and 18 months after the onset of disease. (Korobeynikov et al., 2022)

#FUS mutation P525L averages 13.8 months after onset of respiratory failure (Zhou et al., 2020).

Dosage: Intrathecal injection (12 doses in 10 months)

Remarks: Pathologically, the abnormal accumulation of FUS protein in the spinal cord was reduced markedly; however, there was no improvement compared to that in the natural history of this mutation.

Clinical trial status: Phase III

ClinicalTrials.gov Identifier: NCT04768972

Recruiting participants

Expected completion: March 2024

BIIB078, Afinersen

Mode of action: Suppresses C9orf72* expression by ASO

Clinical trial results: ALSFRS-R (progression of symptoms) remained unchanged.

The Biogen Phase I trial BIIB078 showed safety but no clinical benefit (ALSFRS-R, %VC, etc.), and development was discontinued.

ClinicalTrials.gov Identifier: NCT03626012　

Dosage: Intrathecal injection (8 doses in 17 months)

WVE-004

Action: Suppresses C9orf72* expression by ASO.

Clinical Trial Results: Wave Life Sciences Phase I (NCT04931862)　Cerebrospinal fluid showed a decrease in the abnormal protein (polyGP) expressed by the biomarker C9orf72 mutation.

ClinicalTrials.gov Identifier: NCT04931862　

Participants are being recruited

Expected completion: February 2023

CNM-Au8

Action: Promotes cellular energy generation and eliminates oxidative stress.

Current status of clinical trial: Phase II electrophysiological evaluation showed reduced progression; ALSFRS-R was suppressed by a 6-point decline.

Details

Action: Oral suspension of gold nanocrystals (13 nm in diameter). The surface catalyzes energy-generating reactions (increases in NAD+ and ATP) and eliminates oxidative stress.

Current status of the study: Phase 2, randomized, double-blind, placebo-controlled trial (23 actives, 22 placeboes): The primary endpoint of ALSFRS-R and secondary endpoints of Combined Assessment of Function and Survival (CAFS) and slow vital capacity (SVC) were not met at 24 weeks. However, in an exploratory analysis of a long-term open-label extension study (OLE), survival data showed a 62% reduction in the risk of death compared to that in the no treatment or delayed treatment groups (first randomized to placebo) (HR 0.291; p=0.015).

Dosage: Oral administration

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