Takeda is advancing TAK-861, a small molecule compound targeting orexin deficiency, as a potential treatment for narcolepsy. The drug, an orexin receptor-2 agonist, has shown promising Phase IIb data, particularly in narcolepsy type 1 (NT1), the most severe form of the condition caused by a loss of orexin neurons. Phase III trials are currently enrolling patients to further evaluate its efficacy and safety.
Targeting Orexin Deficiency in Narcolepsy
NT1 is characterized by the loss of orexin neurons, leading to low levels of orexin neuropeptides in the brain and cerebrospinal fluid. This deficiency results in symptoms such as excessive daytime sleepiness, cataplexy, vivid dreams, hallucinations, and disrupted nighttime sleep. TAK-861 aims to restore what is missing by modulating the orexin receptor 2, a target that has proven challenging for drug developers over the years.
Elena Koundourakis, Head of Takeda’s Orexin Franchise Development and Neuroscience Programs and Portfolio Strategy, expressed enthusiasm about the potential of TAK-861 to provide hope and peace of mind to patients. "TAK861 is our lead orexin receptor-2 agonist, which is enrolling patients in phase III trials. Phase IIb data in narcolepsy type one (NT1) showed the potential to provide transformational efficacy," she stated.
From TAK-994 to TAK-861: Learning from Experience
Takeda's earlier attempt, TAK-994, an oral orexin receptor agonist, was discontinued due to hepatotoxicity after reaching Phase IIb. However, the efficacy data from TAK-994 were groundbreaking, as published in the New England Journal of Medicine in July 2023. This knowledge and experience were quickly translated into the development of TAK-861.
Potential Benefits and Ongoing Trials
TAK-861 is designed to be taken daily to sustain its effect, improving wakefulness during the day without causing nighttime insomnia. Data also suggest that it can improve secondary symptoms such as cataplexy. "The dose feels right because it's enough to keep you awake during the day, but not so much that it keeps you awake at night. In the morning, you get up and you're ready to go," Koundourakis explained.
Utilizing Wearable Technology for Enhanced Diagnosis
Takeda is collaborating with Beacon Biosignals to use a wearable device, the "Dreem" headband, to track sleep patterns at home. This aims to improve the diagnosis and monitoring of sleep-wake disorders like narcolepsy. Traditional polysomnography requires patients to attend sleep labs, which can be burdensome and limited in availability. The at-home device offers a more accessible and convenient alternative.
"We wanted an at-home test that could alleviate the burden of sleep labs and provide insights earlier," Koundourakis noted. The wearable technology helps in understanding the journey to diagnosis and confirming whether a patient is an NT1 patient, which has a distinct sleep architecture in polysomnography.
Expanding Beyond NT1
Takeda is also exploring the potential of orexin modulation in other conditions, such as obstructive sleep apnea, which often overlaps with and masks the diagnosis of narcolepsy. By leveraging wearable technology and AI, the company aims to maximize data and incorporate it into product development, providing solutions for patients with multiple sleep-wake disorders.
Addressing a Significant Unmet Need
NT1 is not something that therapists can address, and patients often experience comorbidities such as depression, anxiety, and cognitive issues like brain fog. TAK-861 is seen as a low-dose solution with few side effects, potentially treating both the main symptoms and the underlying pathophysiology of the disease.
"Tak-861 is the difference between a lot of drugs that treat a little bit of the wakefulness, and a single drug that helps with all the symptoms," Koundourakis stated, emphasizing the potential of the drug to transform the way narcolepsy is treated. The focus is now on completing Phase III trials and navigating the regulatory process to bring this promising therapy to patients in need.
