Dalzanemdor, formerly SAGE-718, fails to aid cognition in Phase 2 trial

Sage stops developing the therapy for mild cognitive impairment in Parkinson's

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by Steve Bryson, PhD |

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Sage Therapeutics’ dalzanemdor, formerly known as SAGE-718, an investigational oral medication for mild cognitive impairment (MCI) due to Parkinson’s disease, has failed to outperform a placebo in a Phase 2 study.

Based on these top-line data from the trial, called PRECEDENT (NCT05318937), Sage will stop any further development of dalzanemdor for Parkinson’s.

“We are disappointed by the results of the Phase 2 PRECEDENT study given the significant burden of mild cognitive impairment on people and families affected by Parkinson’s Disease,” Barry Greene, Sage’s CEO, said in a company press release. “We are thankful for the patients and healthcare professionals who participated in this research.”

Parkinson’s is characterized by the progressive loss of nerve cells that produce dopamine, a key signaling chemical in the brain. One of dopamine’s functions is to regulate the activity of N-methyl-D-aspartate (NMDA) protein receptors, which are essential for proper nerve cell communication, a process involved in cognitive function.

Damage to dopamine-producing cells in Parkinson’s is thought to disrupt NMDA signaling and drive cognitive impairment.

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Dalzanemdor designed to modulate NMDA receptor activity

Dalzanemdor is designed to modulate NMDA receptor activity with the goal of restoring nerve cell communication and cognitive processes in Parkinson’s patients.

Early data from the open-label Phase 2 PARADIGM study (NCT04476017) showed the therapy, given once daily, was associated with gains in thinking and memory in 11 people with Parkinson’s and mild cognitive impairment.

Building on these findings, Sage launched PRECEDENT, also called CNP-202, which enrolled 86 adults with MCI due to Parkinson’s and mild to moderate motor problems. Participants were assigned randomly to receive oral dalzanemdor capsules, or a matching placebo, once daily in the morning for 42 days, or six weeks.

Top-line data showed the study did not meet its primary endpoint of demonstrating a statistically significant improvement in cognitive function compared with the placebo, as assessed by the Wechsler Adult Intelligence Scale-IV. This standard assessment measures cognitive function that correlates with the ability to accomplish everyday tasks.

The analyses also showed no meaningful differences versus the placebo in the other exploratory endpoints, such as the Scales for Outcomes in Parkinson’s Disease-Cognition.

The therapy was well tolerated, with 48 patients experiencing treatment-emergent adverse events, which were deemed mild to moderate in severity.

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Sage developing dalzanemdor for cognitive deficits in Huntington’s, Alzheimer’s

Sage is developing dalzanemdor for cognitive impairment due to other neurodegenerative conditions, including Huntington’s and Alzheimer’s diseases.

“Although cognitive impairment is common in neurodegenerative disorders, the underlying pathophysiology and symptomatology in Parkinson’s disease is distinctive, and these results do not necessarily predict results with dalzanemdor in other neurodegenerative conditions,” Greene said.

Two Phase 2 clinical trials, called DIMENSION (NCT05107128) and SURVEYOR (NCT05358821), are testing the therapy in people with Huntington’s and cognitive impairments. The Phase 2 study LIGHTWAVE (NCT05619692) is evaluating dalzanemdor in people with MCI and mild dementia due to Alzheimer’s.

According to Sage, top-line data from SURVEYOR is expected by June, while data from DIMENSION and LIGHTWAVE are anticipated by the end of the year.

Greene added, “We look forward to the topline data readouts from the Phase 2 studies in Huntington’s disease and Alzheimer’s disease expected later this year.”