Biogen and Sage Terminate Development of SAGE-324 Following Disappointing Phase 2 Data

Laura Gault, MD, PhD

Newly announced data from the phase 2 KINETIC 2 study (NCT05173012) showed that treatment with investigational SAGE-324, also known as BIIB124, did not demonstrate statistically significant results on the study’s primary end point in participants with essential tremor (ET). As a result of these data, Biogen and Sage Therapeutics, the drug manufacturers, have decided to close the open-label safety study and terminate the development of SAGE-324 as a treatment for ET.¹

The trial featured 147 patients with ET who were randomly assigned to either placebo or SAGE-324 in doses of 15 mg, 30 mg, and 60 mg for a 3-month period. After 91 days of treatment, the investigational agent failed to distinguish itself from placebo on the primary end point of change in Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale (PS) Item 4 (upper limb) total score.

SAGE-324, an oral neuroactive steroid GABAA receptor positive allosteric modulator, failed to demonstrate a dose-dependent relationship on the primary end point. In addition, between the treated groups, there was no statistically significant difference in change from baseline in TETRAS Activities of Daily Living Composite Score, a secondary end point. As a result of these data, the companies are evaluating next steps, if any, for other potential indications.

"There has been little innovation in the pharmacological treatment of essential tremor over the past 50 years, and people living with this debilitating condition have a pressing need for new treatment options,” Laura Gault, MD, PhD, chief medical officer at Sage, said in a statement.¹ "We are disappointed that the results of the KINETIC 2 Study do not support further development of SAGE-324 in ET. We are grateful to the essential tremor community and study investigators for their contributions to this research. As always, Sage remains steadfast in our work to develop new treatments for people suffering from brain health conditions."

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In addition to failing to meet the primary end point, investigators observed a dose-relationship between the incidence of central nervous system depressant treatment-emergent adverse events (TEAEs) and frequency of TEAEs leading to study drug discontinuation. Overall, the most common reported TEAEs from any treatment group were somnolence, dizziness, fatigue, feeling abnormal, headache, and balance disorder. The company noted that the majority of TEAEs were mild or moderate in intensity.

Data from the phase 2 KINECTIC trial (NCT04305275), a previously completed study, showed a significant decrease in upper limb tremor in treated patients relative to placebo after 29 days. The data, published in Movement Disorders earlier this year, showed a statistically significant reduction from baseline on TETRAS-PS Item 4 score in SAGE-324-treated patients vs placebo (–2.3 [SE, 0.401] vs –1.24 [SE, 0.349]; P = .0491). Notably, in a prespecified subgroup analysis of patients with severe baseline TETRAS-PS Item 4 score (at least 12), researchers reported that treatment with SAGE-324/BIIB124 produced a significant LSM reduction from baseline at day 29 versus placebo (–2.75 [SE, 0.426] vs. –1.05 [SE, 0.412]; P = .0066).

In the study, 69 patients aged 18 to 80 were randomly assigned 1:1 to orally receive 60 mg of SAGE-324 (n = 34) or placebo (n = 35) once daily for 28 days. Authors observed secondary end point improvement in TETRAS-PS Item 4 scores with SAGE-324/BIIB124 compared with placebo across all other time points, but besides day 29, this had only been nominally significant at day 8 (LSM reduction, –0.86 [SE, 0.273] vs. –1.67 [SE, 0.287]; P = .0468). In the SAGE-324/BIIB124 group, the most common TEAEs included somnolence (67.6%), dizziness (38.2%), fatigue (14.7%), balance disorder (14.7%), diplopia (11.8%), dysarthria (11.8%), and gait disturbance (11.8%). Only 3 patients from the SAGE-324/BIIB124 group reported 1 or more treatment-emergent serious adverse events (SAE) of mental status change, dehydration, headache, and/or transient ischemic attack.

REFERENCES
1. Sage Therapeutics and Biogen Announce Topline Results from Phase 2 KINETIC 2 Study of SAGE-324 (BIIB124) for the Treatment of Essential Tremor. News release. Sage Therapeutics. July 24, 2024. Accessed July 24, 2024. https://investors.biogen.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-topline-results-phase-2
2. Elble RJ, Ondo WG, Lyons KE, et al. A Randomized Phase 2 KINETIC Trial Evaluating SAGE-324/BIIB124 in Individuals with Essential Tremor. Mov Disord. 2024;39(4):733-738. doi:10.1002/mds.29731