Biogen, Sage discontinue essential tremor drug after mid-stage failure

Biogen and Sage Therapeutics announced on Wednesday that their Phase II study of SAGE-324 for treating essential tremor did not meet its primary endpoint. Consequently, the companies stated that no further development of the oral drug, known also as BIIB124, will occur for essential tremor, although other potential uses may still be investigated.

The clinical trial, termed KINETIC 2, assessed various doses of SAGE-324 for its effect on upper limb tremor in 147 participants diagnosed with essential tremor. The primary measure of success was the change from baseline at day 91 on the Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale Item 4 total score. Unfortunately, the top-line results revealed no statistically significant differences between any dose of SAGE-324 and placebo. The study's secondary endpoint, which focused on the TETRAS Activities of Daily Living composite score, also did not show any notable improvements.

In addition, Biogen and Sage mentioned that there was no dose-response relationship for SAGE-324 regarding the primary endpoint. However, a dose-relationship was noted in the occurrence of treatment-emergent adverse events (TEAEs) related to the central nervous system (CNS), and in the frequency of TEAEs leading to discontinuation of the study drug. The most common TEAEs across all treatment groups included somnolence, dizziness, fatigue, feeling abnormal, headache, and balance disorder, with most of these adverse events being mild to moderate in severity.

Laura Gault, the chief medical officer of Sage Therapeutics, expressed disappointment in the results, stating that the data from KINETIC 2 do not support further development of SAGE-324 for essential tremor. The news had immediate financial repercussions, with Sage's shares dropping by 21% in pre-market trading on Wednesday. SAGE-324 is identified as an investigational neuroactive steroid GABAA receptor positive allosteric modulator.

Previous studies had shown some promise for SAGE-324. In an earlier mid-stage KINETIC study, the drug demonstrated a significant reduction in tremor scores compared to placebo in essential tremor patients at day 29. However, roughly two-thirds of the patients taking 60 mg of the drug had to reduce their dosage due to adverse events. KINETIC 2 was structured as a dose-ranging trial beginning at 15 mg, with Sage’s CEO Barry Greene previously indicating hopes that the efficacy observed at three months would match earlier findings.

Greene had emphasized the importance of finding an optimal benefit-risk dose for chronic administration, which was a key objective for KINETIC 2. The trial's inability to meet the primary endpoint prevents the companies from moving forward with SAGE-324 for essential tremor.

In 2020, Biogen had committed $875 million upfront and agreed to take an equity stake in Sage to co-develop SAGE-324 for essential tremor, along with zuranolone, which has since been approved under the brand name Zurzuvae for depression.

The failure of the KINETIC 2 study underscores the complex challenges inherent in drug development, especially in finding effective treatments for conditions like essential tremor. While the future of SAGE-324 for this particular indication appears to be at an end, the exploration of other potential uses for the drug remains a possibility.