Policy & Regulation
SAGE-324 Phase 2 Placebo-Controlled KINETIC Study in Essential Tremor Met Primary Endpoint
13 April 2021 - - US-based biopharmaceutical company Sage Therapeutics, Inc. (NASDAQ: SAGE) and neuroscience specialist Biogen Inc. (NASDAQ: BIIB) have reported topline results from the Phase 2 KINETIC Study evaluating SAGE-324 in the treatment of people with essential tremor, the company said.

The study (n=67 full analysis set) achieved its primary endpoint of a statistically significant reduction from baseline compared to placebo in The Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale Item 4 upper limb tremor score on Day 29 (P=0.049), which corresponded to a 36% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE-324 compared to a 21% reduction in patients receiving placebo.

Activities of daily living scores showed a statistically significant correlation with upper limb tremor score at all timepoints.

While not powered to fully examine TETRAS ADL, SAGE-324 was numerically superior to placebo at all time points. Reported treatment-emergent adverse events (TEAEs) were generally consistent with the safety profile of SAGE-324 to date.

In the KINETIC Study, patients with a more severe tremor at baseline (at or above the median TETRAS Performance Subscale upper limb tremor Item 4 score of 12) who received SAGE-324, demonstrated a statistically significant reduction (P=0.007) from baseline in TETRAS Performance Subscale Item 4 upper limb tremor score compared to placebo at Day 29, corresponding to a 41% reduction from baseline in upper limb tremor amplitude in patients receiving SAGE-324 compared to an 18% reduction for placebo. Study patients were not taking other medications for ET during the 28-day treatment period.

The collaboration partners are pleased with the progress to date and are planning next steps for development of SAGE-324.

Full data from the KINETIC Study will be shared at future scientific forums and in publications.

In the KINETIC Study, SAGE-324 taken orally, once daily in the morning, showed a statistically significant reduction from baseline in upper limb tremor score as measured by Item 4 of TETRAS Performance Subscale on Day 29 compared to placebo.

TETRAS Scale includes two subscales: the Performance Subscale and the Activities of Daily Living Subscale.

The TETRAS Performance Subscale is a validated, physician-administered scale designed to provide an accurate, comprehensive assessment of ET motor symptoms and has been shown to correlate with TETRAS ADL. The Performance Subscale includes Item 4, which measures upper limb tremor.

Patients receiving SAGE-324 experienced a statistically significant reduction from baseline in TETRAS Performance Subscale Item 4 compared to placebo at Day 29 (P=0.049), 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.

The analysis is based on the prespecified Full Analysis Set.

Patients were randomized 1: 1 to receive SAGE-324 (60 mg) or matched placebo once daily in the morning. The trial evaluated treatment of SAGE-324 at the higher end of the dose range and the daily dose could be down-titrated to 45 mg or 30 mg if 60 mg was not well tolerated.

Down-titration of dose occurred in 62% of patients who received SAGE-324 and discontinuations were noted in 38% of patients receiving SAGE-324.

Adverse events were generally consistent with the safety profile of SAGE-324 seen to date.

The most common TEAEs that occurred in ≥10% 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%.

The KINETIC Study is a Phase 2 study that evaluated the efficacy, safety, and tolerability of SAGE-324 60 mg in 69 patients with essential tremor aged 18 to 80 years old. The primary endpoint of the multicenter, randomized, double-blind, placebo-controlled study was change from baseline compared to placebo on Day 29 in upper limb tremor score as measured by Item 4 of the TETRAS Performance Subscale.

Essential Tremor is one of the most common movement disorders in the United States, affecting an estimated 6.4m Americans.

For ET patients, uncontrollable shaking of the hands, head, voice, or legs creates difficulty eating, dressing, writing, and pursuing other day-to-day tasks.

While ET is often associated with aging populations, ET can begin much earlier in life, with a progressive disease course that can eventually necessitate a care partner.

Social anxiety and depressive symptoms can manifest in patients with ET as tremor severity increases and may negatively impact a patient's ability to work and engage in hobbies.

The only US Food and Drug Administration approved pharmacological treatment for ET was approved more than 50 years ago, and more than 50% of patients with ET experience a sub-optimal response with standard-of-care treatments, highlighting a significant unmet need in care.

SAGE-324 is an investigational oral neuroactive steroid GABAA receptor positive allosteric modulator. NAS GABAA receptor PAMs bind to both synaptic and extrasynaptic GABAA receptors, enhancing inhibitory activity of the GABAergic system, the major inhibitory neurotransmission system in the brain.

GABA is the primary inhibitory neurotransmitter in the central nervous system and plays a critical role in maintaining balanced neuronal activity in the brain. GABA dysregulation has been implicated in the pathophysiology of ET.
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