The trial did not meet its primary endpoint of slowing disease progression as measured by ALSFRS-R or secondary endpoints related to muscle strength and respiratory function. What do these results suggest about the challenges of targeting the integrated stress response (ISR) in ALS therapy?

Pending data on neurofilament light (NfL) and other biomarkers are expected later in 2025. How might these analyses help clarify the potential role of DNL343 in modifying disease biology or guide future research directions?

Subgroup analyses could offer critical insights. What key factors or patient characteristics would you expect to emerge as potential predictors of response to DNL343, and how might these guide future trials?

DNL343 was found to be safe and well tolerated, with good cerebrospinal fluid penetration. How important are these findings in maintaining momentum for future investigations, despite the lack of efficacy in primary and secondary endpoints?

The HEALEY ALS Platform Trial is unique in its collaborative and adaptive design. How does this approach contribute to advancing ALS research, even when individual regimens, like DNL343, show limited efficacy?

DNL343 targets eIF2B to reduce stress granule formation and TDP-43 buildup, key pathological features in ALS. Given the trial outcomes, how viable is stress granule modulation as a therapeutic strategy for ALS?

Active treatment extension data is anticipated later in 2025. How critical will these long-term findings be in understanding the full potential of DNL343 and its impact on disease progression or biomarkers?

What lessons can be drawn from the DNL343 trial for future ALS therapeutic development, and how can researchers refine approaches to address the unmet needs of the ALS patient community?