DNL343

Denali Therapeutics is a US biotech company developing medicines for neurodegenerative diseases. It provided DNL343 to the HEALEY ALS Platform Trial as Regimen G and later wound down the programme.

When cells are stressed, they switch on the integrated stress response, which slows protein production and can lead to clumps called stress granules. In ALS these are linked to TDP-43, a protein that clumps in motor neurons. DNL343 activates eIF2B, a protein that helps turn this stress response off, in the hope of protecting neurons.

Denali announced in January 2025 that DNL343 missed its main and secondary goals. In March 2025 it reported no effect on neurofilament light, a blood marker of nerve damage, and stopped the extension study. HEALEY researchers later said further study of DNL343 in ALS is not warranted.

The January 2025 topline results showed no benefit, and a follow-up analysis showed no effect on nerve-damage markers. Denali stopped the extension and HEALEY investigators concluded further ALS study was not warranted.

In the trial, 186 people received DNL343 and 139 received placebo for 24 weeks. The published results showed a disease rate ratio of 1.04, where 1.0 means no difference, so decline was about the same as placebo. It also did not lower neurofilament light.

This is the most favourable result reported. See all key studies for the full picture.

The HEALEY trial enrolled adults with ALS at sites across the USA. People in this arm took 200 mg of DNL343 by mouth each day, or placebo.

DNL343 is not available and no ALS trials are recruiting. The active treatment extension was stopped in 2025.