SAGE-319

Sage’s final hope to turn its business around has failed, leaving the future of the once high-flying company and its postpartum depression drug uncertain. The company announced Wednesday morning that a Phase 2 study for dalzanemdor, previously known as SAGE-718, failed in Huntington’s disease, saying it missed the primary and all secondary endpoints. As a result, Sage will stop all further dalzanemdor development and suspend an ongoing open-label safety study in Huntington’s. With the failure, Sage has no remaining ongoing clinical trials. The company scuttled the rest of its pipeline and some early-stage research last month, its second restructuring since August 2023, when its postpartum depression drug Zurzuvae won approval but was also rejected in the broader major depression population. Zurzuvae notched $11 million in third-quarter sales. A spokesperson told Endpoints News in an email that Sage will use the study “to inform our go-forward R&D strategy and continue to evaluate options across our early-stage pipeline, including SAGE-319,” a program the company says is in Phase 1 development but does not appear on the clinicaltrials.gov registry. Zurzuvae remains Sage’s “core strategic focus,” the spokesperson added. Wednesday’s readout comes after warning signs flashed on dalzanemdor all year. In July, Sage adjusted the primary endpoint in the trial after a separate study showed only a “small numerical difference” between the drug and placebo on the previous primary endpoint, which measured cognitive decline. Dalzanemdor also failed to improve cognition in mid-stage studies of Alzheimer’s and Parkinson’s disease , but execs and analysts believed the Huntington’s trial had been the drug’s best shot at success. The new primary endpoint also looked at cognition but was focused on a subgroup of the original measurement, a broader composite cognitive assessment called HD-CAB. Sage’s stock price $SAGE fell as much as 18% in Wednesday’s premarket session, but rose to about a 2% decline off Tuesday’s close before trading was halted.

Sage Therapeutics is reeling from another mid-stage setback as its investigational medicine dalzanemdor has missed the mark in a Phase 2 mild cognitive impairment trial. The drug, an NMDA receptor positive allosteric modulator, was not significantly better than placebo at helping Alzheimer’s patients with mild cognitive impairment or mild dementia improve on a scale known as the Wechsler Adult Intelligence Scale Fourth Edition Coding Test. Dalzanemdor had failed on the same primary endpoint in another Phase 2 in patients with Parkinson’s disease this spring. At the time, Sage executives tried downplaying any read-through from the Parkinson’s trial to the Alzheimer’s study. The 12-week trial, dubbed LIGHTWAVE, randomized 174 Alzheimer’s patients. With the primary endpoint miss, Sage said it is discontinuing further development of dalzanemdor, or SAGE-718, in Alzheimer’s. Sage’s share price $SAGE was down more than 12% before Tuesday’s opening bell. Next up is Huntington’s disease. The Cambridge, MA-based biotech said it anticipates reporting topline results from another Phase 2 of the investigational drug in patients with cognitive impairment associated with Huntington’s by the end of this year. The drugmaker said that is its lead indication for the medicine. “While we are disappointed by the results of the LIGHTWAVE Study, we are grateful to participants, investigators, care partners, patient advocates and the Alzheimer’s community who helped make this important research possible,” CEO Barry Greene said in a press release. “We hope our work and these findings help to inform future research.” It marks another blow to Sage’s pipeline. In July, the company and partner Biogen said their oral medicine SAGE-324 failed a Phase 2 in essential tremor . Biogen walked away from that piece of their pact two months later. Sage continues to evaluate whether SAGE-324 can be applied for other brain conditions. The duo secured an FDA green light for their drug Zurzuvae in postpartum depression last August, but it was rejected in the broader population of major depressive disorder. Sage is also evaluating a slate of other investigational medicines, including SAGE-689, SAGE-421 and SAGE-319.