The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult-onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small-molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.

Keywords: ALS preclinical strategies; amyotrophic lateral sclerosis; clinical trials; edaravone; riluzole.

Figure 1.. Anti-excitatory treatment clinical treatment strategies for ALS. Lamotrigine, mexiletine and riluzole inhibit voltage-gated sodium channels.

Riluzole furthermore inhibits the release of glutamate into the synaptic cleft through sodium channel-independent mechanisms. Retigabine is an activator of voltage-gated potassium channels. Gabapentin and nimodipine inhibit voltage-gated calcium channels. Memantine is an NMDA receptor antagonist approved for the symptomatic treatment of Alzheimer’s disease. Perampanel and telampanel are AMPA receptor inhibitors. Ceftriazone promotes the uptake of glutamate by astrocytes while the COX2 inhibitor celecoxib inhibits the release of glutamate from astrocytes.

Figure 2.

Anti-excitatory small molecules in clinical trials for ALS.

Figure 3.

Antioxidants small molecules in clinical trials for ALS.

Figure 4.. Anti-inflammatory clinical treatment strategies for ALS.

Astrocytes, microglia and T cells promote inflammation in ALS, causing immune cell infiltration and production of inflammatory cytokines. Anti-inflammatory strategies suppress pro-inflammatory signaling. Ono-2506 suppresses astrogliosis. Various small molecules are under investigation that suppress microglial activation including masitinib (inhibitor of CSF-1R), fasudil (ROCK1 inhibitor), DNL747 (RIPK1 inhibitor) and the PDE inhibitors pentoxyfilline and ibudilast. Several therapeutics are aimed at suppressing NF-kB signaling through various and sometimes unknown mechanisms including CC100, NP001, pioglitazone (an approved drug for the treatment of diabetes) and RNS60. Minocycline suppresses microglial cytokine production through unknown mechanisms. Thalidomide decreases levels of TNFα. Other therapies are aimed at suppressing T cell response including antibodies that target interleukin receptors 1 (anakinra) and 6 (tocilizumab) and thus suppress signaling through these receptors. Glatiramer acetate is mixture of peptides resembling myelin basic protein, a drug approved for the treatment of multiple sclerosis that modulates the reactivity of T cells. IL-2 peptide activates regulatory T cells that modulate T cell response.

Figure 5.

Anti-inflammatory/immune-modulatory small molecules in clinical trials for ALS.

Figure 6.. The actin-myosin cross-bridge enables muscle contraction.

(A) Relaxed muscle. The actin-binding site partially occluded by tropomyosin, preventing myosin from binding fully. (B) Muscle contraction. Ca²⁺ binds to troponin, causing a conformational shift that causes tropomyosin to unblock the actin-binding site. Myosin binds to the accessible binding site (actin-myosin cross-bridge). Small-molecule troponin binders increase sensitivity to Ca²⁺, thus increasing the force of muscle contraction.

Figure 7.. Small molecules in clinical trials for ALS.

(A) Troponin binders, (B) SOD1-targeting small molecules, (C) autophagy enhancers.

Figure 8.. Small molecules in clinical trials for ALS.

(A) Xaliproden, a small-molecule neurotrophic factor, (B) modulators of mitochondrial function.

Figure 9.. TDP-43-dependent loss of stathmin-2.

(A) in healthy cells, nuclear TDP-43 binds to a cryptic splicing site in intron 1 of stathmin-2 pre-mRNA. Intron 1 (and following introns) are spliced and the mature mRNA contains all exonic sequences. (B) Upon TDP-43 depletion, the cryptic exon (E_c), which harbors a premature polyA site, is included in the mRNA transcript, resulting in truncation of the transcript and loss of expression of Stathmin-2 protein.

Figure 10.. Hsp104 is a protein disaggregase.

Hsp104 extracts misfolded proteins from soluble oligomers, amyloid fibrils, and amorphous aggregates and returns them to a natively folded state in an ATP-dependent manner. Humans (or any other members of the animal kingdom) have no Hsp104 homolog. Thus, a therapeutic disaggregase strategy would depend on delivery of Hsp104 or DNA encoding Hsp104 exogenously. Potentiated Hsp104 variants have been engineered with enhanced activity against different misfolded proteins.

Figure 11.. RAN translation of dipeptide repeats in C9ORF72-ALS.

G₄C₂ hexanucleotide repeat expansions in intron 1 of the C9ORF72 gene are translated in the absence of a start codon (repeat-associated non-ATG translation). Translation from the sense and antisense strand yields five dipeptide repeats (poly-GR, poly-GP, poly-GA, poly-PR, poly-PA). Dipeptide repeats have detrimental effects in cells, causing heterochromatin abnormalities, translational stalling, disturbed LLPS and cytotoxicity. Preclinical therapeutic strategies are aimed at suppressing RAN translation.