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Discussing the Efficacy of SAGE-324 in Treating Essential Tremor

Helen Colquhoun, MD, vice president of early development at Sage Therapeutics, commented on results from a phase 2 study in which patients receiving SAGE-324 showed a significant decrease in ET.

Results from the phase 2 KINETIC trial (NCT04305275) were presented at The International Parkinson and Movement Disorders (MDS) Society Virtual Congress 2021, September 17-22, finding that SAGE-324 (also known as BIIB124), an investigational, oral neuroactive steroid GABAA receptor positive allosteric modulator, met its primary end point of decreasing upper limb tremor in patients with essential tremor (ET) from baseline at day 29, when compared to patients who received placebo. Patients were evaluated on change from baseline score of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale item 4 (upper limb tremor score) after treatment with SAGE-324 for 28 days.

Treatment for ET is of vital importance, according to Helen Colquhoun, MD, vice president, early development at Sage Therapeutics, as it can interfere with normal activities of everyday life and leave patients feeling embarrassed, which is compounded by the need to be more reliant on caregivers. Colquhoun spoke with NeurologyLive on takeaways from the KINETIC study, noting that data “exceeded our expectations.” Further discussed were future plans for the treatment, which is anticipated to be studied in a phase 2 dose-ranging trial later this year, as well as her impressions from the virtual MDS Congress overall. 

NeurologyLive: Can you provide an overview of the findings/data that were presented at the conference? Were any findings surprising in any way?

Helen Colquhoun, MD: We were pleased to present positive data from the KINETIC Study at MDS, showing that SAGE-324 met the primary endpoint in the KINETIC study. In the study, patients who received SAGE-324 experienced a statistically significant reduction from baseline in TETRAS Performance Subscale Item 4 compared to placebo at day 29 [P = .049], corresponding to a 36% reduction in upper limb tremor amplitude from baseline in the SAGE-324 group compared to a 21% reduction in the placebo group.

Further, for patients with a more severe tremor at baseline—patients at or above the median TETRAS Performance Subscale upper limb tremor Item 4 score of 12 or higher—SAGE-324 demonstrated a significant reduction from baseline in TETRAS Item 4 upper limb score at day 29 compared to placebo [P = 0.007] that corresponded to 41% reduction from baseline in tremor amplitude at day 29, compared to an 18% reduction for placebo. Of note, these patients comprised the majority of patients in the study and represent the most significant unmet need.

Additionally, in the study, activities of daily living scores showed a statistically significant correlation with upper limb tremor score at all timepoints. From a clinical point of view, this is an important consideration, and we are encouraged by these data.

In the trial, adverse events were generally consistent with the safety profile of SAGE-324 seen to date. The most common TEAEs [treatment-emergent adverse events] that occurred in 10% or more of patients in the SAGE-324 treatment group and at a rate at least twice as high as that of patients in the placebo group were: somnolence (68%), dizziness (38%), balance disorder (15%), diplopia (12%), dysarthria (12%), and gait disturbance (12%).

 We believe the tremor reduction seen in the KINETIC Study is clinically meaningful. 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.

These data exceeded our expectations. We are now focusing on next steps for the ongoing development of SAGE-324 in essential tremor along with our collaborators at Biogen.

How will this affect patient care, if successful, for those with essential tremor? Is there something that makes the drug unique?

SAGE-324 was selected as the lead compound in our neurology franchise partly because of the predicted good oral bioavailability and long plasma half-life in humans. These 2 attributes have now been confirmed in our early clinical studies. Additionally, our early studies with SAGE-324 have shown a striking pharmacokinetic/pharmacodynamic relationship: as plasma concentrations of SAGE-324 increase after a single dose, the tremor amplitude decreases. The correlation between upper limb tremor score and the activities of daily living score in KINETIC supports the clinical relevance of the findings.

 This is important because 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.

 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. The abilities to write and perform fine motor tasks are commonly impacted and activities related to self-care, such as cooking and getting dressed, get increasingly difficult for patients, with more and more reliance on assistance from caregivers.

What are the future plans for SAGE-324/BIIB124? Are there any plans in place for another study? 

We are progressing the SAGE-324 program and expect to initiate a phase 2 dose-ranging study in late 2021, with the goal of optimizing the dosing regimen with a good tolerability profile and a dosing schedule to maintain plasma concentrations that translate into sustained tremor symptom control. We believe the pharmacologic characteristics of SAGE-324 are well-suited to address unmet needs for people with ET.

What is your biggest takeaway from this year's MDS Virtual Congress about the direction that the field is headed?

My biggest take away is the need for and importance of innovative treatments to address the needs of people living with essential tremor. People with brain health disorders have been conditioned to accept the status quo due to limited innovation or the lack of truly transformative medicines in recent years—and that’s certainly been the case with essential tremor. However, at Sage, we believe that people suffering from brain health disorders deserve better and we aim to help achieve that.

Transcript edited for clarity. For more coverage of MDS 2021, click here.

REFERENCE
Bankole K, Takahashi K, Qin M, Colquhoun H, Eible RJ. SAGE-324/BIIB124, an oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM), in patients with essential tremor: results from the phase 2 KINETIC trial. Presented at MDS Congress 2021; September 17-22; Virtual. Poster LBA 10.