Dalzanemdor work stopping after Phase 2 trial fails at cognitive gains
No significant changes seen with treatment; Bayer also halts gene therapy work
Sage Therapeutics is discontinuing the development of dalzanemdor after the investigational therapy failed to improve cognitive abilities relative to a placebo among people with Huntington’s disease enrolled in a Phase 2 clinical trial.
Statistically significant gains in cognition with treatment was the main goal of the DIMENSION (NCT05107128) study, which also failed to meet secondary trial goals, it announced.
“We are disappointed by the results of the DIMENSION Study, especially for the individuals and families affected by Huntington’s Disease who have long awaited new treatment options,” Barry Greene, CEO of Sage, said in a company press release.
Therapy targeted nerve cell receptors to aid cognition in Huntington’s
The company also is closing its ongoing and open-label Phase 3 PURVIEW trial (NCT05655520), intending to assess the long-term safety and exploratory efficacy of dalzanemdor in a larger group of Huntington’s patients.
Dalzanemdor, formerly known as SAGE-718, is designed to modulate NMDA receptors, a group of proteins found at the surface of nerve cells that are involved in learning and memory.
Impaired NMDA receptor activity is believed to contribute to neurodegeneration in Huntington’s and other neurological diseases, and Sage believed that by increasing the receptors’ sensitivity, dalzanemdor would improve cognitive function. Cognitive problems, particularly, are among the most common symptoms of Huntington’s.
DIMENSION was designed to explore the effects of dalzanemdor in people with Huntington’s-associated cognitive impairment. It enrolled 189 adults, ages 25-65, who were randomly assigned to once daily oral capsules of either dalzanemdor or a placebo for 12 weeks, or about three months.
The study’s main goal was to evaluate changes in performance on the symbol digit modalities test (SDMT), a widely used measure of cognitive function.
Top-line trial data found no significant changes in test of cognitive function
Newly announced top-line data showed no significant differences in SDMT scores between dalzanemdor-treated patients and those given a placebo over those three months, meaning the trial failed to meet its primary goal.
Patients also completed a battery of other tests of cognitive and functional status as secondary outcome measures. Results here also showed no statistically significant or clinically meaningful differences between the dalzanemdor and placebo groups.
Dalzanemdor was well tolerated, without new safety signals identified, Sage noted, and most reported adverse events were mild or moderate in severity.
“Innovation is desperately needed, and we are immensely grateful to the participants, investigators, and the entire Huntington’s Disease community whose unwavering commitment to advancing research helped make this study possible,” Greene said.
Sage also test its experimental oral therapy in people with other neurodegenerative diseases, including Parkinson’s and Alzheimer’s, and findings in those Phase 2 trials likewise showed dalzanemdor failed to improve cognition in either patient group.
Earlier this year, however, Sage reported that a smaller Phase 2 Huntington’s trial, called SURVEYOR (NCT05358821), found trends toward cognitive and functional improvements in patients after about a month of once daily dalzanemdor treatment, supporting the larger DIMENSION study.
Gene therapy’s safety, efficacy was being evaluated in a clinical trial
In other news, Bayer announced that it is stopping developmental work on its Huntington’s gene therapy candidate AB-1001, also known as BV-101.
AB-1001 uses a modified adeno-associated virus to deliver directly to brain cells in targeted regions a copy of the gene that encodes the production of CYP46A1, a neuron-specific enzyme involved in cholesterol metabolism.
Its development was based on data indicating that people with Huntington’s have unusually low CYP46A1 levels, leading to abnormal cholesterol accumulation that contributes to disease progression.
Asklepios Biopharmaceutical, a Bayer subsidiary, launched an initial Phase 1/2 trial (NCT05541627) of AB-1001 in 2022. The study was designed to assess the gene therapy’s safety and preliminary efficacy in adults with early Huntington’s disease, and it was reported to have enrolled five patients at a single site in France.
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