Sage Therapeutics and Biogen have extended the pharma industry’s multi-decade essential tremor losing streak. Three years after tolerability overshadowed efficacy, the partners have given up on SAGE-324 in the indication after failing to reduce tremors in a phase 2 trial designed to address their earlier problems.
Investigators randomized 147 patients to receive one of three doses of SAGE-324, also called BIIB124, or placebo. After 91 days of daily dosing, people taking SAGE-324 fared no better than their peers receiving placebo on a measure of upper limb tremors. The result caused the study to miss its primary endpoint. SAGE-324 failed to show a statistically significant dose-response relationship on the primary endpoint.
Sage and Biogen responded to the results by closing an open-label study examining the safety of SAGE-324. The partners have no plans to run further clinical trials of the candidate in essential tremor but are yet to give up completely. Evaluations of whether to pursue other indications are ongoing.
Investors made their judgment, sending shares in Sage down 27% to below $10 in premarket trading. Biogen’s stock slipped 1% to below $222. The moves reflect the reevaluation of a prospect that Biogen added to its pipeline in a deal worth $1.5 billion upfront. Sage was in line to receive up to $520 million in regulatory and commercial milestones, plus up to $300 million in paydays tied to net sales, for the asset.
The setback could extend the essential tremor community’s long wait for a new pharmacological option. While the FDA has approved devices in the indication in recent years, the agency last authorized a drug to treat the condition in the 1960s.
Gaps in understanding of the biology of essential tremor have hindered efforts to treat the condition. Multiple studies have implicated GABA dysfunction in essential tremor, encouraging Sage to go after the indication. But the failure raises questions about whether GABAA receptor positive allosteric modulators can move the needle.
Sage saw reductions in tremor amplitude when it tested 60 mg of SAGE-324 in an earlier trial. However, tolerability problems led Sage to switch administration from the morning to the evening, trial two lower doses and up-titrate to the top, 60-mg dose.
The failure to retain the efficacy signal after making the changes continues a rotten run for developers of essential tremor drug candidates. Neurocrine Biosciences dropped a candidate after seeing phase 2 data in 2022, Praxis Precision Medicines reported a midphase failure in 2023 and Jazz Pharmaceuticals added to the litany of failures in 2024. Praxis moved into phase 3 despite the midphase primary endpoint miss.
William Blair analysts dubbed SAGE-324 "not essential," in a Wednesday morning note.
Mizuho's Uy Ear said the miss was likely to weaken the Sage/Biogen collaboration and questioned whether the companies' joint work on postpartum depression med Zurzuvae would be enough for the deal to survive.
Editor's Note: This story was updated at 10:45 a.m. on July 24, 2024, to include analyst commentary.