Latest ALS Clinical Trial Information

(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.