Corcept Therapeutics' selective cortisol modulator, dazucorilant, failed to meet its primary endpoint in the Phase 2 DAZALS trial for amyotrophic lateral sclerosis (ALS), but showed a statistically significant survival benefit. The randomized, double-blind, placebo-controlled study involved 249 patients across the U.S., Canada, and Europe, evaluating two doses (150 mg and 300 mg) of dazucorilant over 24 weeks.
The DAZALS trial aimed to slow the decline in motor skills and other functional criteria, as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). While the primary endpoint was not met, a notable observation was the reduced mortality rate in the 300 mg dazucorilant arm, with no deaths reported (0/83) compared to five deaths (5/82) in the placebo group (p-value: 0.02) during the 24-week study period.
Safety and Tolerability
Patients receiving dazucorilant experienced a higher incidence of gastrointestinal upset at the onset of treatment compared to those on placebo. This side effect may warrant consideration in future studies and clinical use.
Ongoing Extension Study
An open-label, long-term extension study is currently underway, where all participants receive 300 mg of dazucorilant. Overall survival will be assessed in March 2025, one year after the onset of treatment for all patients. This extension study will provide further insights into the long-term effects of dazucorilant on survival and disease progression.
Mechanism of Action and Rationale
Dazucorilant is a selective cortisol modulator that binds to the glucocorticoid receptor, aiming to mitigate the harmful effects of excessive cortisol levels, which have been increasingly linked to ALS, particularly in patients with rapid disease progression. Preclinical studies in animal models of ALS demonstrated that dazucorilant reduced inflammation and prevented nerve cell damage, also improving motor function and reducing muscle wasting.
Implications for ALS Treatment
ALS, also known as Lou Gehrig’s disease, is a fatal neurodegenerative disorder affecting over 55,000 individuals in the United States and Europe. The disease leads to muscle weakness and impairs speaking, eating, moving, and breathing, with a typical life expectancy of two to five years post-diagnosis. The observed survival benefit, despite the failure to meet the primary endpoint, suggests a potential neuroprotective effect of dazucorilant, warranting further investigation into cortisol modulation as a therapeutic strategy for ALS.
Future Directions
Corcept plans to present complete results from the DAZALS study at an upcoming medical conference. Further research is needed to understand the mechanisms underlying the observed survival benefit and to confirm these findings in larger clinical trials. The FDA has granted Fast Track Designation to Dazucorilant, which is meant to accelerate the development and review of medicines for serious conditions.
