HEALEY ALS Platform Trial

What is the drug thought to do? 

ABBV-CLS-7262 activates the protein complex eIF2B, which regulates the cell stress response. This 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 toxic protein clumps in the neurones. A previous trial has shown that ABBV-CLS-7262 increased eIF2B activity and suppressed the stress response.

What is the drug thought to do? 

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 toxic protein clumps in the neurones. It is thought that DNL343 may inhibit the stress response and reduce the formation of these toxic clumps.

What is the drug thought to do in the body?

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. 

Outcome

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. 

What is the drug thought to do in the body?

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. 

Outcome

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.

What is the drug thought to do in the body?

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.

Outcome

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 who received the placebo. However, CNM-Au8 was found to show a potential survival benefit. The potential survival benefit is consistent with results from the Phase 2 RESCUE-ALS study. You can read more in a press release.

Additional results from the trial suggested a reduction in a marker of nerve damage, called neurofilament light chain, between those receiving CNM-Au8 and placebo at the end of the trial. Some people receiving CMN-Au8 also showed a drop in neurofilament levels compared to baseline. These results are yet to be published in a peer-reviewed journal.

What is the drug thought to do in the body?

Pridopidine is a Sigma-1 receptor agonist, which means it activates the receptor causing a biological response. Sigma-1 receptor regulates key cellular pathways which are known to be damaged in MND. The activation of the Sigma-1 receptor has been shown to be protective to motor neurones in laboratory studies. 

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.

What is the drug thought to do in the body?

A characteristic sign of MND is clumps of proteins accumulating in motor neurone cells. One way that these clumps can be disposed of is through autophagy – which is the cells waste disposal mechanism. Trehalose can activates autophagy, to help increase the disposal of these protein clumps. Laboratory studies, in models of MND, showed trehalose delayed the onset of disease and prolonged survival.

Outcome

The primary endpoint of the Trehalose reigme was not met. This suggests that there was no significant change in ALSFRS-R scores (from baseline to 24 weeks) for those who received the treatment compared to those who received placebo (dummy drug). There were also no differences found in secondary endpoints, such as muscle function and respiratory measures. You can read more about the results in a press release.

May 2024 - The trial completes enrollment for 7th arm DNL-343. You can read more here. 

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

March 2024 - The primary endpoint for the Trehalose regime was not met, suggesting the treatment is not beneficial for people with MND. Read more in a press release. 

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