Treatments for Disease Modification in Development

The numerous possible disease-modifying therapies that are being researched:

Modification of the genome

Modification of genetic expression to enhance neuronal development and repair is a hot topic in the search for new therapies. Tofersen, an antisense oligonucleotide (ASO) that decreases SOD1 levels by inhibiting SOD1 mRNA translation, has shown some promise in clinical studies in people with ALS who have SOD1 mutations. In another form of hereditary motor neuron disease, spinal muscular atrophy (SMA), the use of ASOs has proved highly helpful. 

Stem Cells 

Because motor neuron cell death is the major etiology of ALS, the use of stem cells has emerged as a viable treatment approach. Mesenchymal stem cells that produce neurotrophic factors are being studied in a phase 3 clinical study (MSC-NTF). In a recent phase 2 clinical study, lower inflammatory biomarkers and a slowed fall in ALSFRS-R scores demonstrated safety and promising effectiveness. 

Activators of Skeletal Muscles

Muscle weakness is one of the more severe symptoms of ALS, and it's an excellent target for therapy. Skeletal muscle activators are being studied for this purpose, as they activate troponin and therefore indirectly improve the calcium sensitiveness of the muscle sarcomeres. Three similar treatments have recently been studied in clinical trials: tirasemtiv, reldesemtiv, and levosimendan. Tirasemtiv increased slow vital capacity in a phase 3 study, although this was not statistically significant, and disease progression as evaluated by the ALSFRS-R did not improve. 8 In phase 2 studies, both levosimendan and reldesemtiv failed to show substantial effectiveness in alleviating ALS symptoms. 9 Despite these findings, both reldesemtiv and levosimendan are still being studied, with phase 3 studies planned.

Modulators of the Immune System

Immune-modulating medicines are a significant target of therapy research in ALS because inflammatory mechanism increases neuronal death. Tocilizumab, masitinib, ibudilast, and ravulizumab are among the immunomodulators now being tested in clinical studies. Both tocilizumab and masitinib have shown promise in early studies, with tocilizumab decreasing ALSFRS-R score deterioration and masitinib regulating inflammation in people with sporadic ALS.   In a phase 2 study for the treatment of multiple sclerosis, another neurodegenerative illness, Ibudilast reduced brain atrophy. 2 In the forthcoming Healey platform study, the verdiperstat and immunomodulators zilucoplan will be used. This novel platform trial strategy will evaluate many possible treatments at the same time with a common placebo group, reducing costs and trial duration while increasing the number of participants.

Agents that protect the brain

In a phase 2 clinical study, tauroursodeoxycholic acid (TUDCA) inhibited programmed cell death and substantially decreased ALSFRS-R score reduction.  Another phase 2 study for TUDCA in conjunction with sodium phenylbutyrate, which is considered to act as a neuroprotective drug via modulating gene expression, has been completed; however, the findings have not been published as of the time of writing this review. Deferiprone is an iron-reducing drug with antioxidant characteristics that may help to halt the progression of ALS. Mecobalamin, an active form of vitamin B12, appears to protect neurons by lowering inflammatory homocysteine levels, and data from a phase 2/3 clinical study suggests that large dosages may slow ALSFRS-R score decrease.   In a recent phase 2 clinical study, arimoclomol, which activates heat shock proteins that serve as chaperones to repair misfolded proteins, similarly decreased ALSFRS-R score degradation. Both metallocomplex copper and microcrystalline gold are being evaluated in the forthcoming Healey platform study to see whether they can minimize oxidative species and enhance mitochondrial function.