Takeda Pharmaceutical has announced positive results from its Phase 2b clinical trial of TAK-861, an investigational oral orexin receptor 2 (OX2R) agonist for narcolepsy type 1 (NT1). The data, presented as late-breaking research at SLEEP 2024, the 38th annual meeting of the American Academy of Sleep Medicine and the Sleep Research Society, demonstrated significant improvements across all measured endpoints.
The randomized, double-blind, placebo-controlled trial enrolled 112 patients with NT1 and evaluated the efficacy and safety of TAK-861 over an 8-week treatment period. The drug is designed to address the underlying pathophysiology of NT1 by targeting orexin deficiency.
Significant Clinical Improvements Across Multiple Measures
The trial met its primary endpoint with statistically significant and clinically meaningful increased sleep latency on the Maintenance of Wakefulness Test (MWT) versus placebo across all doses (p ≤0.001). These improvements were sustained throughout the 8-week treatment period.
Key secondary endpoints also showed positive results, including significant improvements in the Epworth Sleepiness Scale (ESS) scores and Weekly Cataplexy Rate (WCR). By the end of the treatment period, the majority of participants had reached normative ranges for both MWT and ESS measures.
Dr. Sarah Sheikh, Head of Neuroscience Therapeutic Area Unit and Global Development at Takeda, emphasized the potential impact of these findings: "In this trial, TAK-861's profile balanced efficacy and safety with the potential to establish a new standard of care for people with NT1."
Addressing the Underlying Disease Mechanism
NT1 is a chronic neurological disorder characterized by the loss of orexin-producing neurons in the brain, resulting in low levels of orexin neuropeptides. This deficiency leads to debilitating symptoms including excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), disrupted nighttime sleep, hallucinations, and sleep paralysis.
Current treatments for NT1 manage symptoms but do not address the underlying orexin deficiency. TAK-861 represents a potential paradigm shift as the first oral orexin receptor 2 agonist that could directly target the disease's pathophysiology.
Safety Profile and Tolerability
The safety results indicated that TAK-861 was generally well-tolerated, with no treatment-related serious adverse events or discontinuations due to adverse events reported. The most common treatment-emergent adverse events included insomnia, urinary urgency and frequency, and salivary hypersecretion. Most adverse events were mild to moderate in severity, typically beginning within 1-2 days of treatment initiation and resolving over time.
Notably, no cases of hepatotoxicity or visual disturbances were reported in either the Phase 2b trial or the ongoing long-term extension study, where some patients have reached one year of treatment.
Patient-Reported Outcomes
Beyond the primary clinical measures, exploratory endpoints revealed meaningful improvements in narcolepsy symptoms and functioning according to most participants. Additional data on function, health-related quality of life, and patient satisfaction with TAK-861 treatment were presented in poster sessions at the conference.
The majority of participants who completed the trial chose to enroll in the long-term extension study, suggesting a positive patient experience with the treatment.
Regulatory Status and Future Development
Based on these promising results, Takeda plans to initiate global Phase 3 trials of TAK-861 in NT1 in the first half of its fiscal year 2024. The U.S. Food and Drug Administration (FDA) has already granted Breakthrough Therapy designation for TAK-861 for the treatment of excessive daytime sleepiness in NT1, which will expedite the development and review process.
TAK-861 is the leading program in Takeda's orexin franchise, which includes multiple orexin agonists targeting various sleep disorders. The company is also advancing TAK-360, an oral OX2R agonist for narcolepsy type 2 and idiopathic hypersomnia, and danavorexton (TAK-925), an intravenously administered OX2R agonist being investigated for obstructive sleep apnea.
Potential Impact on Patient Care
For the estimated 1 in 2,000 people affected by narcolepsy, TAK-861 could represent a significant advancement in treatment options. The debilitating symptoms of NT1 can severely impact quality of life, job performance, academic achievement, and personal relationships.
If approved, TAK-861 would be the first treatment to directly address the orexin deficiency underlying NT1, potentially offering more comprehensive symptom relief than current therapies that primarily manage individual symptoms rather than addressing the disease mechanism.
As Takeda advances TAK-861 into Phase 3 trials, the medical community will be watching closely to see if these promising early results translate into a transformative therapy for people living with this challenging neurological disorder.
