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.

The zilucoplan regimen was ended early after the trial was evaluated as part of the regular interim analyses. At the most recent interim analysis, zilucoplan was found to have a low probablilty of meaningfully slowing disease progression. You can read more here. 

The primary endpoint of the verdiperstat regime was not met. This meant that participants randomised to Verdiperstat did not have a statistically significant slowing of disease progression as measured by ALSFRS-R over 24-weeks compared to participants randomised to placebo. There were also no statistically significant benefits for other measures including muscle strength, respiratory function and survival. Full study results are expected to be released later in the year. You can read more in a press release.

The primary endpoint of the CNM-Au8 regime was not met. This meant that participants randomised to CNM-Au8 did not have a statistically significant slowing of disease progression as measured by ALSFRS-R over 24 weeks compared to participants randomised to placebo. However, CNM-Au8 was found to show a potential survival signal, with those randomised to 30 mg of CNM-Au8 demonstrating a >90% reduction in risk of death. The potential survival signal is consistent with results from the Phase 2 RESCUE-ALS study which also demonstrated a reduction in the risk of death. You can read more in a press release.

Additional results from the trial were released in June 2023. A statistically significant reduction of a marker of nerve damage, called neurofilament light chain (NfL), was observed for those who received 24-weeks of treatment with CNM-Au8 compared to placebo. However, comparisons to baseline levels of NfL have not been reported. Further analysis in underway to understand more about what these results may mean. You can read more in a press release.

The primary endpoint of the Pridopidine regimen was not met. This meant that participants randomised to pridopidine did not have a statistically significant slowing of disease progression as measured by ALSFRS-R over 24 weeks compared to participants randomised to placebo. However, pridopidine was found to have a potential greater benefit for those who were within 18 months of symptom onset with a definite or probable ALS diagnosis.

The mechanism of action of the drug suggest it may have benefits for people living with MND with bulbar and speech related symptoms. The trial found improvements in speaking rate and articulation rate for those who took pridopidine compared to those who took placebo. You can read more about the results in a press release.

April 2024 - The trial completes enrollment for 6th arm ABBV-CLS-7262. You can read more here.

June 2023 - Additional results from the CNM-Au8 arm were announced. A statistically significant reduction of a marker of nerve damage, called neurofilament light chain (NfL), was observed for those who received 24-weeks of treatment with CNM-Au8 compared to placebo. Further analysis in underway to understand more about what these results may mean. You can read more in a press release.

May 2023 - First participants are enrolled onto the 7th arm of the trial, DNL343. You can read more here. 

March 2023- First participants are enrolled onto the 6th arm of the trial ABBV-CLS- 7262. You can read more here.

Feb 2023 - Results from the Pridopidine arm were announced. Unfortunately the primary endpoint was not met, however a potential benefit for those who were within 18 months of symptom onset was observed. The trial also suggested it may have benefits for people living with MND with bulbar and speech related symptoms. You can find out more here. 

Feb 2023 - The trial completes enrollment for 5th arm Trehalose. You can read more here.

Oct 2022 - Results from the CNM-Au8 arm were announced. Unfortunately the primary endpoint was not met, however a potential survival benefit for those who received the treatment was observed. You can find out more here. 

Sept 2022  - Results from the Verdiperstat arm were announced. Unfortunately the primary endpoint was not met. You can find out more here. 

March 2022  - Zilucoplan arm stopped early for futility. You can find out more here. 

Feb 2022 - 5th arm SLS-005 (Trehalose) enrolled its first participants. You can find out more here. 

Jan 2022 - The trial completes enrollment for 4th arm Pridopipine. You can find out more here. 

Nov 2021 - The trial completes enrollment in the first 3 arms. You can read more here. 

• Improving clinical trial design - MND Research Blog

• HEALEY ALS Platform Trial (massgeneral.org)

• Latest News & Updates from the HEALEY ALS Platform Trial