After previously failing studies in Parkinson’s and Alzheimer’s, dalzanemdor’s latest stumble in Huntington’s disease has pushed Sage Therapeutics to pull the plug on the NMDA receptor modulator.
Sage Therapeutics will cease development of dalzanemdor after the embattled neurodegenerative asset missed the primary endpoint in a Phase II trial for Huntington’s disease, the biotech announced Wednesday.
Dalzanemdor, an investigational allosteric NMDA receptor modulator Sage had also previously been developing for Alzheimer’s disease and Parkinson’s disease, failed to significantly improve cognitive function in adult patients with Huntington’s in the Phase II DIMENSION study.
With this mid-stage stumble, Sage will also discontinue the ongoing open-label PURVIEW study, which is primarily assessing the safety of dalzanemdor in Huntington’s disease.
Shares of the Cambridge, Mass.–based company dropped around 3% in premarket trading.
Topline results from DIMENSION showed that at 84 days, treatment with dalzanemdor did not result in a statistically significant improvement from baseline in the Symbol Digit Modalities Test, a validated tool used to measure sustained attention, processing speed, visual scanning and motor speed. Dalzanemdor treatment also failed to show statistically significant or clinically meaningful benefits in terms of secondary endpoints.
CEO Barry Greene said in a statement that the biotech is “disappointed” by these findings, “especially for the individuals and families affected by Huntington’s Disease who have long awaited new treatment options.”
Designed to be taken orally, dalzanemdor is a positive allosteric modulator of the NMDA receptor that had first-in-class potential for Huntington’s disease. This mechanism of action has largely failed to pan out in the clinic, however. In June 2024, Sage released Phase II data for dalzanemdor in Huntington’s noting that the drug candidate beat placebo at improving cognition in Huntington’s disease patient, though only by a slight margin.
At the time, William Blair analysts called the findings “underwhelming,” adding that they “do not view the small numerical changes as definitive” evidence of dalzanemdor’s activity.
It’s been a rough road for dalzanemdor. The NDMA receptor modulator failed in Parkinson’s disease, with a mid-stage readout in April 2024 showing it was unable to significantly improve scores in the Wechsler Adult Intelligence Scale Fourth Edition-IV Coding Test at 42 days. The Phase II study also found no meaningful benefit to dalzanemdor treatment in all of its exploratory endpoints, which included a cognitive assessment. Sage discontinued the program.
A few months later, in October 2024, the company reported another stumble for dalzanemdor. Data from the Phase II LIGHTWAVE study showed that Alzheimer’s disease patients treated with the candidate did not see significant improvements in intelligence as compared with placebo. Sage has also since terminated the development of dalzanemdor in Alzheimer’s.
In a somewhat positive spin, Stifel analyst Paul Matteis said the discontinuation of the Huntington’s program does likely free up some additional capital for Sage.
Sage also recently enacted a cost-cutting initiative, which included laying off 165 employees, or about 33% of its workforce.
As the launch of postpartum depression drug Zurzuvae “continues to chug along, the question of ‘what’s next’ becomes very salient for SAGE,” Matteis said.
