Biogen, Sage fail essential tremor trial, extending wait for new option

Shares in Sage Therapeutics fell by 27% to below $10 in premarket trading, marking a significant setback for the company and its partner Biogen. This decline comes after the two companies decided to abandon SAGE-324, also known as BIIB124, as a treatment for essential tremor, following disappointing results from a phase 2 clinical trial.

In the study, 147 patients were randomized to receive one of three doses of SAGE-324 or a placebo. After 91 days of daily dosing, the results showed that those taking SAGE-324 did not experience a significant reduction in upper limb tremors compared to those on the placebo. The trial failed to meet its primary endpoint, as there was no statistically significant dose-response relationship observed.

As a result of these findings, Sage and Biogen have ceased an open-label study that was examining the safety of SAGE-324. While they do not plan to pursue further clinical trials for essential tremor with this candidate, they are still evaluating whether to explore other indications for the drug.

The market response was swift and severe; shares in Sage plummeted 27%, dropping below $10. Biogen’s stock also took a hit, falling by 1% to below $222. This sharp decline reflects the reevaluation of a project that Biogen had committed to with a $1.5 billion upfront investment. Sage also stood to gain up to $520 million in regulatory and commercial milestones, along with an additional $300 million tied to net sales of the drug.

The failure of SAGE-324 is a significant blow not only for Sage and Biogen but also for the essential tremor community, which has been waiting decades for a new pharmacological treatment. Although the FDA has approved devices for essential tremor in recent years, the last drug approval for the condition came in the 1960s.

The underlying challenges in understanding the biology of essential tremor have been a major stumbling block. Studies have pointed to GABA dysfunction as a contributor to the condition, motivating Sage's pursuit of the indication. However, the latest failure casts doubt on whether GABAA receptor positive allosteric modulators can be effective in treating essential tremor.

Earlier trials showed some promise, with reductions in tremor amplitude noted at a 60 mg dose of SAGE-324. However, due to tolerability issues, Sage adjusted the treatment regimen, switching dosing times and testing lower doses. Unfortunately, these adjustments did not retain the initial efficacy signal.

This latest setback continues a troubling trend for the development of essential tremor treatments. Neurocrine Biosciences, Praxis Precision Medicines, and Jazz Pharmaceuticals have all faced similar failures in recent years. Praxis, despite a midphase failure, has moved into phase 3 trials, indicative of the persistent challenges in this therapeutic area.

Analysts have been critical of the results. William Blair analysts labeled SAGE-324 as "not essential," while Mizuho's Uy Ear suggested that this failure could weaken the Sage-Biogen collaboration. There are also questions about whether their joint efforts on the postpartum depression medication Zurzuvae will be sufficient to sustain the partnership.

In summary, the failure of SAGE-324 in the phase 2 trial and the subsequent market reaction underscore the complexities and challenges in developing effective treatments for essential tremor. The pharma industry’s long-standing struggle in this area continues, leaving both companies and patients in search of viable solutions.