HEALEY ALS Platform Trial

There is evidence to support that complement system (part of the immune system) activation plays a role in MND. This activation cause damage to tissues in the central nervous system. Zilucoplan is a inhibitor of part of this complement system, known as complement component 5. This prevents any tissue damage caused by the activation of the complement system. 

One of the hallmarks of neurodegeneration in MND is the presence of large numbers of activated microglia. Microglia are the primary immune cells of the central nervous system. When these microglia are activated it results in the presence of myeloperoxidase (MPO) which is believed to increase oxidative stress and inflammation in the brain and spinal cord. Verdiperstat is an inhibitor of MPO and has the potential to reduce microglial activation. 

CNM-Au8 is an oral liquid suspension of gold nanocrystals designed to improve nerve cells’ survival, function, and communication by supporting their energetic needs, while lowering oxidative stress. Preclinical studies showed that CNM-Au8 improved nerve cell survival and motor neuron function in rodent models of MND and other neurodegenerative diseases, such as multiple sclerosis, and Parkinson’s disease.

Pridopidine is a Sigma-1 receptor agonist, which means it activates the receptor causing a biological response. Sigma-1 receptor regulates key cellular pathways and is known to be impaired in neurodegeneration. The activation of the Sigma-1 receptor has been shown to exert neuroprotective effects in pre-clinical trials. 

A characteristic sign of MND is clumps of proteins accumulating in motor neurone cells. One way that this clumps can be disposed of is through autophagy – which is the cells waste disposal mechanism. Trehalose can activate autophagy and potential help to treat MND. Pre-clinical trials have shown it to delay onset of disease and prolong survival.

ABBV-CLS-7262 activates the protein complex eIF2B, which regulates the cell stress response. The stress response is a critical process that helps to control the function of the cell when it is exposed to stressful conditions. It is thought to be constantly activated in MND and may contribute to the formation of TDP-43 clumps in the neurons. A previous trial has shown that ABBV-CLS-7262 increased eIF2B activity and suppressed the stress response, which could lead to reduced TDP-43 aggregation.

DNL343 targets the protein complex eIF2B, which regulates the cell stress response. The stress response is a critical process that helps to control the function of the cell when it is exposed to stressful conditions. It is thought to be constantly activated in MND and may contribute to the formation of TDP-43 clumps in the neurons. It is thought that DNL343 may inhibit the stress response and dissolve some of the TDP-43 containing stress granules, which lead to the formation of TDP-43 aggregates in MND.