Denali Therapeutics’ ALS Therapy Fails to Meet Primary Endpoint in Phase II/III Trial
US-based biotechnology company Denali Therapeutics has reported that a Phase II/III trial of DNL343 for amyotrophic lateral sclerosis (ALS) failed to meet its primary endpoint.
Trial Design and Objectives
The trial, part of the HEALEY ALS Platform trial, aimed to assess changes in disease severity over time using the ALS Functional Rating Scale-Revised, as well as survival rates up to week 24. The primary analysis included 186 subjects who received the therapy and 139 subjects who were given a placebo.
Trial Objectives
- Primary Endpoints: Evaluate changes in disease severity over time using the ALS Functional Rating Scale-Revised, as well as survival rates up to week 24.
- Secondary Endpoints: Assess respiratory function and muscle strength, with no significant difference between the therapy and placebo groups at the 24-week mark.
Trial Results
Denali reported that the therapy was safe and well-tolerated among subjects. However, the trial failed to meet its primary endpoint, with no significant differences in disease severity or survival rates between the treatment and placebo groups.
Trial Outcomes
- Primary Endpoint: Failed to meet its primary endpoint, with no significant changes in disease severity or survival rates.
- Secondary Endpoints: Showed no significant difference between the therapy and placebo groups at the 24-week mark.
Future Analysis and Next Steps
Denali anticipates further analyses later this year, which will include neurofilament light (NfL) and other fluid biomarkers, as well as data from pre-specified subgroups and extended outcomes from the active treatment extension period.
Upcoming Analyses
- Neurofilament Light (NfL): To be included in future analyses, providing additional insights into disease progression.
- Pre-specified Subgroups: To evaluate the efficacy of DNL343 in specific patient populations.
- Extended Outcomes: To assess the long-term effects of the therapy on disease severity and survival rates.
Company Response
Denali Therapeutics chief medical officer Carole Ho said: "We are deeply grateful to the study participants, investigators, and the broader community for their collective support of the HEALEY study, which has provided an efficient and innovative platform for evaluating the therapeutic potential of DNL343 in addressing this critical unmet need."
Company Statement
- Support for the HEALEY Study: Denali expressed gratitude to all participants, investigators, and supporters.
- Future Analysis: Looking forward to a more comprehensive analysis of the study results as additional analyses become available later in 2025.
DNL343: A Novel Therapeutic Approach
DNL343 is an investigational candidate targeting eukaryotic initiation factor 2B (eIF2B), a key regulator of the integrated stress response. This new small molecule therapeutic approach represents a promising avenue for treating ALS, an adult-onset progressive motor neuron disease.
Targeting eIF2B: A novel approach to addressing ALS, by targeting a key regulator of the integrated stress response.
The HEALEY ALS Platform Trial
The HEALEY ALS Platform trial is a large-scale initiative designed to expedite the development of new ALS treatments. By assessing several investigational therapies concurrently, this study aims to provide a more efficient and innovative platform for evaluating therapeutic potential.
HEALEY ALS Platform Trial: A large-scale initiative aimed at accelerating the development of new ALS treatments.
Conclusion
While the trial failed to meet its primary endpoint, Denali’s commitment to advancing ALS research remains unwavering. Future analyses will provide valuable insights into disease progression and treatment efficacy, paving the way for potential breakthroughs in this critical area of research.
Future Directions: Further analysis and next steps, as outlined by Denali Therapeutics’ chief medical officer, Carole Ho.
