Table 1.
A non-exhaustive list of therapeutic agents in development for ALS.
| Agent | Targeted Mechanism | Mechanism | Results | Phase | Ref. |
|---|---|---|---|---|---|
| Sodium Phenylbutyrate-Taurursodiol | endoplasmic reticulum stress, and mitochondrial dysfunction | Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecule chaperone, alleviating endoplasmic reticulum stress toxicity [17,18]. Taurursodiol recovers mitochondrial bioenergetic deficits through multiple mechanisms, including preventing the translocation of Bax protein into the mitochondrial membrane, thereby decreasing mitochondrial permeability and increasing the cell’s apoptotic threshold [19] | Less functional deterioration measured by the ALSFRS-R score over a 24-week period. Secondary outcomes, including decreases in isometric muscle strength and vital capacity, did not differ significantly between groups | II | [20] |
| Colchicine | Protein aggregates, autophagy, and neuroinflammation | Colchicine could upregulate proteins involved in autophagy, including the TFEB, the TFEB-regulated adaptor protein SQSTM1/p62 and the autophagy player microtubule-associated protein 1A/1B-light chain 3 (LC3). | Ongoing | II | [21] |
| Rapamycin | Autophagy and neuroinflammation | Rapamycin is based on the inhibition of mTORC1. mTORC1 targets regulatory proteins in cell signalling and regulates autophagy by inhibiting the unc-51-like kinase 1 complex. | Ongoing | II | [22] |
| BIIB100 (KPT-350) | Nucleocytoplasmic transport dysfunction | Selective inhibitor of nuclear export that inhibits exportin 1 (XPO1; CRM1). | Ongoing | I | |
| Deferiprone | Iron accumulation | Iron Chelation | Ongoing | II | [23] |
| TIRASEMTIV | Muscle contractility | A FSTA that selectively activates the fast skeletal muscle troponin complex by increasing its sensitivity to calcium | In a phase IIb clinical trial, SVC and muscle strength were found to decline significantly more slowly in tirasemtiv-treated participants. But no significant difference was found in the decline in functional disability as measured by the ALSFRS-R. However, no significant difference in disease progression was demonstrated in the phase III clinical trial. |
II/III | [24,25] |
| Interleukine 2 | Neuroinflammation | Immunomodulatory strategy by promoting Treg expansion, which attenuates neuroinflammation. | A phase IIa study showed that low dose IL-2 is well tolerated and immunologically effective in subjects with ALS [26] | III | [26] |
| Masitinib | Neuroinflammation | Tyrosine kinase inhibitor targets microglia and mast cells through inhibiting a limited number of kinases. Masitinib blocks microglia proliferation and activation, and mast cell-mediated degranulation, the release of cytotoxic substances that might further damage the motor nerves. | A randomised, placebo-controlled phase III trial has previously shown that oral masitinib (4.5 mg/kg/day) slows the rate of functional decline with acceptable safety in ALS patients with an ALSFRS-R progression rate of <1.1 points/month | III | [27] |
| Ibudilast (MN-166) |
Neuroinflammation | Inhibitor of macrophage migration inhibitory factor and phosphodiesterases 3,4,10 and 11 [28,29]. Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines. | Ongoing | II/III | [29,30] |
| Fasudil | Neuroinflammation | Rho kinase inhibitor | Ongoing | II | [31] |
| Ravulizumab | Neuroinflammation | Humanized monoclonal antibody to complement factor 5 which acts to block complement activation | The independent Data and Safety Monitoring Board monitoring committee recommended that the study be discontinued due to lack of efficacy. No new safety findings were observed. | III | [32] |
| Zilucoplan | Neuroinflammation | A small molecule that works aa s C5 complement inhibitor | The The independent Data and Safety Monitoring Board recommended stopping the zilucoplan regimen because the likelihood of meaningfully slowing disease progression was considered low. | III | [33] |
| Anakinra | Neuroinflammation | The monoclonal antibody that works as a IL–1 receptor antagonist | Ongoing | II | |
| Tocilizumab | Neuroinflammation | The monoclonal antibody that works as a IL–1 receptor antagonist | Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients | II | [34] |
| Tofersen (BIIB067) |
Gain of function SOD1 | It is an antisense oligonucleotide (ASO) targeting SOD1 | In the Phase III VALOR study, the primary endpoint as measured by the ALSFRS-R did not reach statistical significance; however, signs of reduced disease progression across multiple secondary and exploratory endpoints were observed | III | [35] |
| BIIB078 | Gain of function C9ORF72 | It is an antisense oligonucleotide (ASO) for C9ORF72-associated ALS | In a Phase I study, BIIB078 was generally well-tolerated. The adverse events were mostly mild to moderate in severity and occurred at a similar rate across BIIB078 and placebo groups. BIIB078 did not meet any secondary efficacy endpoints and it did not demonstrate clinical benefit. Therefore, the clinical program will be discontinued |
I | [36] |
Abbreviations: ALSFRS-R, ALS Functional Rating Scale-revised; FSTA, fast skeletal muscle troponin activator; SVC, slow vital capacity; TFEB, master regulator transcription factor EB.