Treatment with SAGE-324/BIIB124 for essential tremor resulted in adverse events that included somnolence, dizziness, fatigue, and balance disorder.
Helen Colquhoun, MD
(Credit: LinkedIn)
Recently published in Movement Disorders, results from the double-blind, randomized, placebo-controlled, phase 2 KINETIC trial (NCT04305275) assessingSAGE-324/BIIB124 (Sage Therapeutics), an investigational positive allosteric modulator of GABAA receptors, showed a significant decrease in upper limb tremor among patients with essential tremor (ET) compared with the placebo at day 29.1 These findings, previously presented at The International Parkinson and Movement Disorders (MDS) Society Virtual Congress 2021, September 17-22, support the further development of SAGE-324/BIIB124 as a potential treatment for patients living with ET.2
In the trial, investigators observed a statistically significant least squares mean (LSM) reduction from baseline at day 29 in The Essential Tremor Rating Assessment Scale-Performance Subscale (TETRAS-PS) Item 4 score in SAGE-324/BIIB124-treated patient versus placebo (–2.31 [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).
“We believe the tremor reduction seen in the KINETIC study is clinically meaningful,” Helen Colquhoun, MD, senior vice president at Sage Therapeutics, told NeurologyLive® in a previous interview when asked about the results presented at MDS 2021. “This study was designed to start to answer the question of tremor reduction over time vs the promising reduction we’ve previously seen at a single time point. To optimize the likelihood of seeing a drug effect, we dosed at 60 mg, the high-end of the dose range established in phase 1 studies. We also wanted to understand the AE profile at the 60-mg dose.”
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Conducted by senior author Rajesh Pahwa, MD, professor of neurology, and director, Parkinson’s Disease and Movement Disorder Center, University of Kansas Medical Center, and colleagues, 69 patients aged 18 to 80 years were randomly assigned 1:1 to orally receive 60 mg of SAGE-324/BIIB124 (n = 34) or placebo (n = 35) once daily for 28 days between May 2020 and February 2021. The primary end point was the change from baseline in TETRAS-PS Item 4, upper-limb tremor, with SAGE-324/BIIB124 compared with placebo at day 29. The secondary outcomes included change from baseline in TETRAS-PS Item 4 score at other time points, TETRAS-ADL score, TETRAS-PS total score, Kinesia ONE motion sensor score for 3-dimensional arm and hand motion compared with placebo, and incidence of treatment-emergent adverse events (TEAEs) through day 42.
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). Notably, researchers reported that this trend in improvement was not observed among participants at day 42. In patients with a baseline TETRAS-PS Item 4 score of at least 12, SAGE-324/BIIB124 showed a significant LSM reduction in TETRAS-PS Item 4 from baseline at all time points except day 42 compared with placebo (all, P <.05).
All told, nominally significant treatment differences with SAGE-324/BIIB124 versus placebo in TETRAS-ADL total scores were observed at days 8, 15, and 22 (all, P <.05). In addition, the treatment difference with SAGE-324/BIIB124 compared with placebo was 1.37 At day 29 (95% CI, −3.81 to 1.08; P = .2682). Authors noted no significant changes from baseline in TETRAS-PS total scores or Kinesia ONE motion sensor scores with SAGE-324/BIIB124 compared with placebo across time points.
“ET is a serious and progressive condition that often steadily deteriorates over time, leading to social isolation and loss of independence. However, this underserved patient population has witnessed almost no innovation for over 50 years, and more than 50% of patients with ET do not respond optimally to the current standard of care,” Colquhoun said when previously asked about how this could impact care for patients with ET. “When you listen to patients, you realize that the tremor can affect nearly every aspect of day-to-day living and can make the simplest tasks difficult, if not impossible. We’ve learned that tremor can lead patients to feel frustrated and embarrassed, while others are left significantly disabled and unable to fully care for themselves.”
Investigators noted that participants reported at least one TEAE in both the SAGE-324/BIIB124-treated group (97.1%) and the placebo group (57.1%). 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. In the placebo group, only 1 participant reported treatment-emergent SAEs of angina pectoris and dyspnea.
Only 2 of the mental status change SAEs with SAGE-324/BIIB124 were assessed as treatment-related by the investigator, both of which resolved after discontinuation. In patients treated with SAGE-324/BIIB124, 26.5% experienced TEAEs that led to treatment discontinuation, and 11.8% experienced TEAEs that led to study discontinuation. Authors noted that none of the patients who received placebo experienced TEAEs leading to treatment or study discontinuation and no reports of death during the study.
Rajesh Pahwa, MD
(Credit: X)
Limitations noted by investigators in the study included the short treatment duration and the higher treatment discontinuance/dropout rates compared with placebo. Authors also noted that administering SAGE-324/BIIB124 in the morning and at the relatively high dose of 60 mg without uptitration could have potentially contributed to the 11.8% study discontinuance rate. Despite using the study design to minimize bias, the researchers noted that they cannot rule out the occurrence of expectation bias. Based on the results from this study, investigators developed an ongoing phase 2 dose–response trial (KINETIC 2, NCT05173012) that will assess nighttime rather than morning dosing and a gradual uptitration of SAGE-324/BIIB124 to potentially improve tolerability.
In episode 68 of the Mind Moments Podcast, "Updates in Essential Tremor Care," Pahwa had an exclusive interview with NeurologyLive to speak about the current state of treatment for ET, including the therapeutic and surgical options for this population. During the interview, he shared his perspective on the latest advances in clinical care and diagnosis, the role of the patient-physician relationship, and the research into the disease's underlying processes.
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