Small molecule compounds


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 


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 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
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 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. 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 Identifier: NCT05136885
Enrollment complete
Expected completion: October 2023


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


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 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.


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. 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 Identifier: NCT04615923

End of entry

Expected completion: 2022


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


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 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)



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


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. 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. Identifier: NCT04066244


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 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).



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