Dalzanemdor

To see whether Sage Therapeutics’ dalzanemdor can deliver the goods in Huntington’s disease, investors will have to wait for the results of the phase 2 DIMENSION study. It remains to be seen whether Sage Therapeutics’ dalzanemdor can improve function in patients with Huntington's disease. While a phase 2 trial has clarified the science around cognitive decline in patients with the neurodegenerative disorder, analysts have labeled the data on the drug itself as “underwhelming.” The company has lined up the NMDA receptor positive allosteric modulator for four midstage trials across Alzheimer’s, Huntington’s and Parkinson’s diseases, which are all set to read out this year. The first study didn’t deliver the goods in April, failing to show an improvement in cognitive performance among patients with Parkinson’s. The latest top-line results, which come from the phase 2 SURVEYOR study in Huntington’s, was never statistically powered to detect whether dalzanemdor can improve cognitive performance. Instead, the study aimed to use six cognitive tests, known collectively as HD-Cognitive Assessment Battery (HD-CAB), to demonstrate a difference in the cognitive ability of 40 patients with the neurodegenerative disease compared to 29 healthy individuals also enrolled in the trial. Once this main objective was successfully completed, the biotech then treated the Huntington’s disease patients with dalzanemdor or placebo for 28 days. Here, it noticed a “small numerical difference” observed between patients who received dalzanemdor or placebo when measured by HD-CAB. “Other prespecified analyses suggested the potential for directionally positive signals in a number of individual component tests of the HD-CAB and in some functional assessments,” the company added. “Additional work is ongoing to further analyze and understand the data including the relationship of changes in cognition to changes in function.” Sage described dalzanemdor as being generally well tolerated in the trial and said no new safety signals were observed. Eleven of the participants with Huntington’s disease experienced treatment-emergent adverse events, of which the “vast majority” were mild to moderate in severity and none of which led to discontinuations. Safety aside, the nature of today’s trial results mean that dalzanemdor is yet to have any phase 2 data to really shout about, after the drug failed the midstage PRECEDENT trial in Parkinson’s two months ago. In a note this morning, analysts at William Blair described the latest results as “underwhelming.” “While a small numerical change was observed on the HD-CAB between placebo and HD participants, we remain cautious on the asset and do not view the small numerical changes as definitive by any means,” they added in the April 24 note. Judging by Sage’s stock price, which remained around the $10.90 mark in premarket trading this morning, investors are unmoved by this morning’s results. “While symptoms of cognitive impairment can precede motor symptoms by up to 15 years, it is a historically underrecognized aspect of HD and there are no approved treatments for cognitive impairment in HD,” Sage Chief Medical Officer Laura Gault, M.D., Ph.D., said in this morning’s release. “The findings from the SURVEYOR study highlight the extent of cognitive impairment associated with HD and enhance our collective understanding of this devastating disease.” To see whether dalzanemdor can succeed in Huntington’s, which Sage describes as its “potential lead indications,” investors and analysts will have to wait for the results of the phase 2 DIMENSION study. Both DIMENSION and the LIGHTWAVE trial in Alzheimer’s are due to read out this year. The biotech has already dropped its Parkinson’s ambitions for the drug after seeing the PRECEDENT results.

Pictured: 3D rendering of nerve cells and neurological disease/iStock, Ralwel Sage Therapeutics announced Tuesday that its oral NMDA receptor dalzanemdor showed a slight numerical improvement in a small Phase II Huntington’s disease trial, while acknowledging the study was not designed to demonstrate a statistically significant difference between the drug candidate and placebo. The Phase II SURVEYOR study, which included 40 patients with Huntington’s Disease (HD), was designed to investigate the magnitude of cognitive impairment compared to 29 healthy participants, as well as evaluate the safety of dalzanemdor. Sage said the study met its primary endpoint of showing a statistically significant difference, as measured by the HD-Cognitive Assessment Battery (HD-CAB) composite score, at baseline between healthy participants and those with HD prior to treatment with dalzanemdor or placebo. While Sage noted a “small numerical difference” between dalzanemdor and the placebo, using the HD-CAB score on day 28, no complex data was provided. At the same time, the company said other “prespecified analyses” showed potential positive signals and additional work is ongoing to analyze the data. In addition, Sage reported that dalzanemdor was generally well-tolerated and no new safety signals were observed, though 11 participants with HD experienced treatment-emergent adverse events which were mostly mild to moderate in severity. William Blair analysts in a Tuesday note to investors called the results “underwhelming” and said they “remain cautious” on dalzanemdor and “do not view the small numerical changes as definitive” based on the SURVEYOR results. “While we agree that this finding is critical for advancing the understanding of the HD-CAB and for the design of studies of cognitive impairments in HD, it does not provide much data on the activity of dalzanemdor,” the analysts wrote. Sage is also waiting to report topline data for the drug in another HD study as well as treatment with dalzanemdor in Alzheimer’s disease. It’s been a rocky road for dalzanemdor which hit significant stumbling blocks in April. A Phase II trial in Parkinson’s disease did not demonstrate a substantial difference in the Wechsler Adult Intelligence Scale Fourth Edition-IV (WAIS-IV) Coding Test score compared to placebo. The drug candidate also did not reach any exploratory endpoints, with Sage deciding to halt any further development for dalzanemdor in Parkinson’s. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.