TABLE 1.
The mechanism and clinical trials details of 53 new drugs under investigation for the treatment of ALS. Including the phase, countries, status, number of patients, start and (estimated) completion year, registration number, primary and secondary endpoints, the results and reference.
| Candidate | Mechanism | Phase | Status | Country | Patients | Start year | Completion year | Registration number | Primary endpoints | Secondary endpoints | Results | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Anti-apoptotic agents | ||||||||||||
| AMX0035 | reduce ER stress and mitigate mitochondrial dysfunction | Ⅲ | ongoing | United States, France, Germany etc. | 600 | 2021 | 2024 | NCT05021536 | Safety, Tolerability, and ALSFRS-R score | SVC, ALSAQ-40,King’s and MiToS Stages, Ventilation Free Survival, EQ-5D descriptive system and the EQ visual analogue scale [EQ VAS],Long-Term Survival | Ongoing | Amylyx, (2021) |
| Methylcobalamin | eliminate neurotoxic homocysteine | Ⅲ | complete | Japan | 130 | 2017 | 2020 | NCT03548311 | ALSFRS-R score | Survival, FVC, homocystein, MMT, Norris scale, Grip Power, ALSAQ-40 | Slow the change of ALSFRS-R | Oki et al. (2022) |
| SAR443820 | RIPK1 inhibitor | Ⅱ | ongoing | Canada, France, Germany, China, United States | 261 | 2022 | 2025 | NCT05237284 | ALSFRS-R score and CAFS score | SVC, HHD, ALSAQ5, Nfl, TEAE,SAE, PK, survival time | Ongoing | Sanofi, (2022) |
| GDC-0134 | DLK inhibitor | Ⅰ | complete | Canada, Netherlands, United States | 54 | 2016 | 2020 | NCT02655614 | Safety and Tolerability | PK and PD | Not safe | Katz et al. (2022) |
| Anti-inflammatory Drugs | ||||||||||||
| Masitinib | selective tyrosine kinase inhibitor | Ⅲ | ongoing | United States, Denmark, France, Germany | 495 | 2021 | 2023 | NCT03127267 | ALSFRS-R score | ALSAQ-40, CAFS, FVS, HHD, PFS | Ongoing | AB Science, (2017) |
| NP001 | a regulator of macrophage activation | Ⅱb | complete | United States, Canada | 138 | 2016 | 2017 | NCT02794857 | ALSFRS-R score | SVC, Time to tracheotomy, and blood inflammatory biomarkers | Failed, but it slowed the decline of ALSFRS-R score and vital capacity of 40–65 subgroup | Miller et al. (2022a) |
| Verdiperstat | MPO inhibitor | Ⅱ/Ⅲ | ongoing | United States | 167 | 2020 | 2023 | NCT04436510 | ALSFRS-R score | SVC, HHD, survival | Ongoing | Cudkowicz, (2020a) |
| Tegoprubart (AT-1501) | CD40L antibody | Ⅱa | complete | United States, Canada | 54 | 2020 | 2022 | NCT04322149 | Safety and Tolerability | -- | It is safe and well tolerated and can reduce inflammatory biomarkers | (Anelixis Therapeutics, 2020), (Eledon Pharmaceuticals, 2022) |
| BLZ945 | CSF-1R inhibitor | Ⅱ | ongoing | United States, Finland, Sweden | 46 | 2019 | 2024 | NCT04066244 | volume of distribution fot [11C]-PBR28 PET scan | PK | Ongoing | Novartis Pharmaceuticals, (2019) |
| Proleukin (Aldesleukin) | Enhance Treg function | Ⅱ | complete | France and United Kingdom | 304 | 2017 | 2021 | NCT03039673 | Time to death | -- | The results have not been posted, as of 2022.08.02 | Centre Hospitalier Universitaire de Nīmes, (2017) |
| Dimethyl fumarate | increase regulatory T-cells | Ⅱ | complete | Australia | 107 | 2018 | 2021 | ACTRN12618000534280 | ALSFRS-R score | survival, lower motor neuron function, respiratory function, quality of life, safety and tolerablity | Failed | Vucic et al. (2021a) |
| Pegcetacoplan | C3 inhibitor | Ⅱ | ongoing | Japan, United States, France, Germany, Italy | 249 | 2020 | 2024 | NCT04579666 | CAFS score | TEAE, ALSFRS-R score, SVC, time to death, permanent tracheostomy, or permanent assisted, muslce strength, C-SSRS score | Ongoing | Apellis Pharmaceuticals, (2020) |
| ANX005 | C1q antibody | Ⅱa | ongoing | United States, Canada | 24 | 2021 | 2023 | NCT04569435 | TEAE | PK and PD | Ongoing | Annexon, (2021) |
| Zilucoplan | C5 inhibitor | Ⅱ/Ⅲ | stopped | United States | 162 | 2020 | 2022 | NCT04436497 | ALSFRS-R score | SVC, HHD, survival | Failed | (Figueiredo) |
| Ultomiris (ravulizumab) | C5 inhibitor | Ⅲ | stopped | United States, Denmark, France, etc. | 382 | 2020 | 2021 | NCT04248465 | ALSFRS-R score | SVC, Time To Ventilator Assistance-free Survival, TEAE,HDD,Nfl | Failed | AstraZeneca, (2021) |
| MN-166 (ibudilast) | Inhibit PDE4 and MIF | Ⅱb/Ⅲ | ongoing | United States, Canada | 230 | 2020 | 2024 | NCT04057898 | ALSFRS-R score | HHD, ALSAQ-5, Time to survival, TEAE, and Laboratory Values | Ongoing | Oskarsson et al. (2021a) |
| Tocilizumab | IL-6R inhibitor | Ⅱ | complete | United States | 22 | 2015 | 2018 | NCT02469896 | Safety and Tolerability | SVC, ALSFRS-R, HHD, Peripheral Blood Mononuclear Cell (PBMC) Gene Expression, Cytokine Levels in the Plasma, Cytokines and Soluble Interleukin-6 in csf, Peripheral Benzodiazepine Receptor 28 (PBR28) Positron Emission Tomography (PET) | It is safe and well tolerated and can reduce CRP. | Milligan et al. (2021) |
| Antiexcitotoxicity agent | ||||||||||||
| Memantine | NMDA receptor inhibitor | Ⅱ/Ⅲ | ongoing | United Kingdom | 531 | 2020 | 2026 | NCT04302870 | ALSFRS-R score and survival | ECAS, FVC, King’s ALS Clinical stage, HADS, EQ-5D-5L, AE | Ongoing | Wong et al. (2022) |
| Mexiletine | sodium channel blocker | Ⅱ | complete | United States | 20 | 2016 | 2018 | NCT02781454 | Resting Motor Threshold | Short-interval intracortical inhibition, Motor Evoked Potential, Cortical Silent Period, Strength Duration Time Constant, Threshold Electrotonus, Hyperpolarizing Threshold Electrotonus, Superexcitability,Subexcitability, Frequency of Muscle Cramps | It reduced motor neuron excitability | Adiao et al. (2020) |
| Ezogabine | KCNQ channel | Ⅱ | complete | United States | 65 | 2015 | 2018 | NCT02450552 | Short-interval Intracortical Inhibition | Resting Motor Evoked Potential (MEP) Threshold, Motor Evoked Potential, Cortical Silent Period, Intracortical Facilitation, Electrotonus, Strength Duration Time Constant, Recovery Cycle, Muscle Cramping Frequency, hhd, Proportion of Days With Fasciculations, tolerability | It reduced motor neuron excitability | Wainger et al. (2021) |
| Penicillin G/Hydrocortisone | GABA inhibitor | Ⅱ | complete | Netherlands | 16 | 2017 | 2020 | EudraCT number 2017–001983-39 | ALSFRS-R score | lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and AE | Failed | Van Es et al. (2020) |
| Perampanel | AMPA receptor inhibitor | Ⅱ | complete | Japan | 66 | 2017 | 2020 | NCT03019419 | ALSFRS-R score | Manual Muscle Test, FVC | Failed | Aizawa et al. (2022) |
| Regulate integrated stress response | ||||||||||||
| Trazodone | NMDA receptor inhibitor | Ⅱ/Ⅲ | ongoing | United Kingdom | 531 | 2020 | 2026 | NCT04302870 | ALSFRS-R score and survival | ECAS, FVC, King’s ALS Clinical stage, HADS, EQ-5D-5L, AE | Ongoing | Wong et al. (2022) |
| Guanabenz | PPP1R15A/PP1c phosphatase complex inhibitor | Ⅱ | complete | Italy | 201 | 2016 | 2021 | Eudract Number 2014–005367-32 | proportion of patients progressing to higher stages of disease within 6 months | CSF biomarker (creatinine, albumin, tau, pNfH, TDP43, cystatin C, fetuin A, transthyretin, and CD14/S100ß and pNfH/C3) | Slowed the progression, but high adverse events | Dalla Bella et al. (2021) |
| IFB-088(Sephin1) | PPP1R15A/PP1c phosphatase complex inhibitor | Ⅱ | France and Italy | 42 | — | — | — | — | — | have not been approved yet | InFlectis BioScience, (2022) | |
| ABBV-CLS-7262 | eIF2B activitor | Ⅰ | ongoing | United State, Canada | 30 | 2021 | 2023 | NCT04948645 | Safety, Tolerability, and PK | Ccsf PK, safe and tolerability | Ongoing | Calico Life Sciences LLC, (2021) |
| DNL343 | eIF2B activitor | Ⅰb | ongoing | United States, Netherlands | 30 | 2021 | 2023 | NCT05006352 | TEAE | PK | Ongoing | Denali Therapeutics, (2021) |
| Neurotrophic factors and neuroprotection | ||||||||||||
| CNM-Au8 | catalyze for energy metabolism | Ⅱ/Ⅲ | ongoing | United States | 161 | 2020 | 2023 | NCT04414345 | ALSFRS-R score | SVC, Survival, ALSFRS-R | Ongoing | Cudkowicz, (2020b) |
| Pridopidine | sigma-1 receptor agonist | Ⅱ/Ⅲ | ongoing | United States | 163 | 2020 | 2023 | NCT04615923 | ALSFRS-R score | Bulbar Function and speech measured by ALSFRS-R, SVC,HHD,Survival | Ongoing | Cudkowicz, (2020c) |
| ILB® | neurotrophic and myogenic | Ⅱa | complete | Sweden | 13 | 2018 | 2019 | NCT03613571 | Safety, Tolerability, Norris rating scale,FVC, functional rating of autonomous and sensory symptoms, PK and PD | ALSFRS-R score | Safe, well tolerated, and improve the ALSFRS-R score | Logan et al. (2022) |
| G-CSF | inhibit apoptosis, induce neurogenesis, mobilize hematopoietic stem cells (HSCs) and reduce inflammatory activity | Ⅱ | ongoing | Italy | 76 | 2020 | -- | Eudract 2014–002228-28 | ALSFRS-R score | Scale for Testing Muscle Strength,FVC, McGill QoL Questionnaire, Time to death or tracheostomy, Interruption of treatment,SAE | Ongoing | Salamone et al. (2020) |
| Fasudil | Inhibit ROCK | Ⅱa | ongoing | France, Germany, Switzerland | 120 | 2019 | 2023 | NCT03792490 | safery, tolerability | ALSFRS-R score, ECAS, Motor Unit Number Index,SVC, survival,ALSAQ-5 | Ongoing | University Medical Center Goettingen, (2019) |
| Inosine | endogenous antioxidant | Ⅱ | complete | United States | 48 | 2017 | 2020 | NCT03168711 | Safety and tolerablity | -- | Tolerated. The serious AE was reported in 28.57% (4/14) of patients receiving Inosine and 11.11% (1/9) of those receiving placebo | Massachusetts General Hospital, (2017) |
| anti aggregation | ||||||||||||
| AP-101 | SOD1 protein antibody | Ⅱa | Ongoing | United States, Canada, Germany, Korea, Sweden | 63 | 2021 | 2023 | NCT05039099 | Safety and tolerablity | PK and PD, Nfl | Ongoing | AL-S Pharma, (2021) |
| Colchicine | induce the expression of HSPB8 | Ⅱ | Ongoing | Italy | 54 | 2019 | 2022 | NCT03693781 | ALSFRS-R score | TEAE, Tracheostomy-free survival rate, FVC,ALSAQ-40, enhancement of autophagy, stress granules size, number and composition, insoluble species,modifications on extracellular vesicles secretion in blood and CSF, biomarkers of neurodegeneration, biomarkers of inflammation | Ongoing | Mandrioli et al. (2019) |
| Arimoclomol | Enhance the expression of heat shock protein | Ⅲ | complete | United States, Canada, Italy, Germany etc. | 245 | 2018 | 2020 | NCT03491462 | CAFS score | Time to permanent assisted ventilation (PAV)/tracheostomy/death, ALSFRS-R, SVC | Failed | (KemPharm Denmark A/S, 2018), (Inacio, 2021) |
| Rapamycin | mTOR inhibitor | Ⅱ | complete | Italy | 63 | 2017 | 2022 | NCT03359538 | Tregs | safety, ALSFRS-R score, inflammasome, ALSAQ-40,fvc,Tracheostomy-free survival, blood biomarkers, activation and homing capabilities of different T, B, natural killer (NK) cell subpopulations, S6 ribosomal protein, Rapamycin capacity to pass through blood brain barrier | increased Tregs, decreased inflammasome and improved the quality of life | (Azienda Ospedaliero-Universitaria di Modena, 2017), (ENCALS, 2022) |
| Monepantel | mTOR inhibitor | Ⅰ | ongoing | Australia | 12 | 2022 | 2023 | NCT04894240 | PK and Determination of Phase 2 Dose | peripheral blood mononuclear cell phosphorylated ribosomal protein S6 kinase B1 (RPS6KB1) levels, peripheral blood mononuclear cell phosphorylated eukaryotic initiation factor 4 E binding protein 1 (EIF4EBP1) levels, ALSFRS-R, ECAS,SVC, urinary p75 levels MRI,Nfl | Ongoing | PharmAust Ltd, (2022) |
| Tamoxifen | Enhance autophagy through both mTOR dependent and independent pathway | Ⅰ/Ⅱ | complete | China | 20 | 2014 | 2019 | NCT02166944 | ALSFRS-R score | pulmonary function test | Only shortly slow the decline for 6 months. No difference in 12 months | Chen et al. (2020b) |
| Bosutinib | Src/c-Abl kinase inhibitor | Ⅰ/Ⅱ | ongoing | Japan | 25 | 2022 | -- | jRCT2051220002 | Safety, ALSFRS-R score | -- | Ongoing | Haruhisa, (2022) |
| SLS-005 (trehalose) | activateg Transcription Factor EB and FOXO1 transcription factor | Ⅱ/Ⅲ | ongoing | United States | 160 | 2022 | 2023 | NCT05136885 | ALSFRS-R score | SVC,HHD,Survival | Ongoing | Cudkowicz, (2021) |
| Withaferin A | NF-κB Inhibition | Ⅱ | ongoing | Canada | 75 | 2021 | 2022 | NCT05031351 | satey | Short-interval intracortical inhibition, Resting motor threshold, recovery cycle, strength duration time constant | Ongoing | Sunnybrook Health Sciences Centre, (2021) |
| 3K3A-APC | Activate PAR1, inhibit microglia, and repair BBB | Ⅱ | ongoing | Australia | 16 | 2021 | 2022 | NCT05039268 | Safety and Microglial Activation in the Motor Cortex | MRI, Monocyte Activation, Cytokine,Chemokine,Nfl, Soluble CD14, Kynurenine Level | Ongoing | Macquarie University, (2021) |
| AL-001(Latozinemab) | Increase progranulin levels | Ⅱ | ongoing | United States | 45 | 2021 | 2023 | NCT05053035 | safety, tolerability, PK and PD,progranulin | Nfl | Ongoing | Alector, (2021) |
| Tideglusib | GSK-3β inhibitor | Ⅱ | ongoing | Switzerland | 98 | 2021 | 2024 | NCT05105958 | Alanine Aminotransferase | Diarrhea | Ongoing | Geneva University Hospitals, (2021) |
| Gene therapy | ||||||||||||
| Tofersen (BIIB067) | SOD1 mRNA antisense | Ⅲ | ongoing | United States, Canada, France, Japan, Korea, etc. | 150 | 2021 | 2027 | NCT04856982 | Percentage of Participants with Emergence of Clinically Manifest ALS Within 12 Months | Time to Emergence of Clinically Manifest ALS, ALSFRS-R, SVC, Survival,AE, SAE, Nfl, CSF SOD1 | Ongoing | Benatar et al. (2022) |
| ION363/Jacifusen | FUS antisense | Ⅲ | ongoing | United States, Australia, Belgium, Canada, United Kingdom | 77 | 2021 | 2025 | NCT04768972 | ALSFRS-R score, Ventilation Assistance-free survival | ALSSQOL-R, Survival, SVC, HHD, Nfl | Ongoing | Ionis, (2021) |
| WVE-004 | C9ORF72 mRNA antisense | Ⅰ/Ⅱ | ongoing | Australia, Canada, United Kingdom, New Zealand, etc. | 42 | 2021 | 2023 | NCT04931862 | AE | poly-GP,Pharmacokinetic | Ongoing, Reduce poly-GP | (Meglio, 2022b), (Wave Life Sciences Ltd, 2021) |
| BIIB078 | C9orf7 mRNA antisense | Ⅰ | complete | United States, Canada, Netherlands, Switzerland, United Kingdom | 90 | 2020 | 2022 | NCT04288856 | AE and SAE | PK | Safe, but not meet secondary goals. The development is discontinued | (Biogen, 2020), (Hoffman, 2022) |
| BIIB105 | ataxin-2 antisense | Ⅰ | ongoing | United States, Canada, Netherlands, Italy | 70 | 2020 | 2026 | NCT04494256 | AE and SAE | PK and PD | Ongoing | Biogen, (2020) |
| APB-102 | a recombinant AAVrh10 that express anti-SOD1 microRNA | Ⅰ/Ⅱ | — | — | — | — | — | — | — | The details of the trial have not been shared | Pinto, (2021) | |
| Engensis (VM202) | Deliver HGF gene through plasmid | Ⅱa | complete | United States, Korea | 14 | 2021 | 2022 | NCT04632225 | safety | ALSFRS-R, HHD, Accurate Test of Limb Isometric Strength,ALSAQ-40, Patient Global Impression of Change,SVC, Time to all-cause mortality, gene expression differences in muscle atrophy biomarkers | Safe and well tolerated | Helixmith, (2022) |
| Other | ||||||||||||
| Reldesemtiv | fast skeletal muscle troponin activator | Ⅲ | ongoing | United States, Canada, Australia, Germany, etc. | 555 | 2021 | 2024 | NCT04944784 | ALSFRS-R score | FVC,HHD,ALSAQ-40 | Ongoing | Cytokinetics, (2021) |
Note: ALSFRS-R, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised scores; ALSAQ-40, 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire; ALSAQ5, Amyotrophic Lateral Sclerosis Assessment Questionnaire; CAFS, The function and survival score; C-SSRS, Columbia Suicide Severity Rating Scale; ECAS, Edinburgh Cognitive and Behavioural ALS Screen; HADS, hospital anxiety and depression scale; FVC, Forced Vital Capacity; SVC, Slow vital capacity; MMT, Manual Muscle Testing; HHD, Hand-held dynamometry; NfL, Neurofilament light chain; TEAE, Treatmentemergent adverse events; SAE, Serious adverse event; AE, adverse event; PK, Pharmacokinetic; PD, Pharmacodynamics; PFS, Progression free survival; CSF, Cerebrospinal Fluid.