Sage burns Parkinson's bridge, flunking first of 4 midphase tests for key prospect

Sage Therapeutics has set a bad PRECEDENT for dalzanemdor. The therapy failed to improve cognitive ability in a phase 2 Parkinson’s disease study, setting Sage off on the wrong foot at the start of a sequence of readouts that will define the future of the molecule.

The candidate, which is also known as SAGE-718, is an NMDA receptor positive allosteric modulator. Sage identified the molecule as a way to act on areas of cognition involved in learning, memory and executive function, leading to the start of midphase trials in patients with Alzheimer’s, Huntington’s and Parkinson’s. All the studies are scheduled to report data this year. 

Sage kicked off the sequence of data drops Wednesday with results from PRECEDENT, a phase 2 trial that compared dalzanemdor to placebo in 86 people with mild cognitive impairment due to Parkinson's disease. The primary goal was to show if the candidate improves cognitive performance, as measured on the WAIS-IV intelligence test.

Dalzanemdor was no better than placebo by that yardstick, causing the trial to miss its primary endpoint. Sage looked at the effect of the molecule on exploratory endpoints such as a Parkinson’s cognition scale but failed to find meaningful differences versus placebo in those analyses either. 

Sage dropped plans to develop dalzanemdor in Parkinson’s in response to the results but is continuing to work toward readouts in Alzheimer’s and Huntington’s. The biotech expects to report topline data from a Huntington’s trial around the middle of the year. Data from an Alzheimer’s trial and another Huntington’s study are due toward the end of 2024.

Like the failed Parkinson’s trial, the studies are looking at the effect of dalzanemdor on cognition. The Alzheimer’s trial is using the same WAIS-IV endpoint as the Parkinson’s trial. The two Huntington's trials are using (PDF) measures of cognition specific to the disease. 

While all the studies are assessing cognition, Sage sees reasons to believe dalzanemdor may fare better in the Alzheimer’s and Huntington’s trials. CEO Barry Greene said in a statement that “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.”

Alzheimer’s and, in particular, Huntington’s are more homogenous patient populations but the failure in Parkinson’s shook investors, who sent Sage's shares down 26% to $11.50 in premarket trading.

As well as limiting the prospects of dalzanemdor, the failure is an inauspicious start for Sage’s targeting of NMDA, a receptor identified as a second area of focus after GABA.