New data suggest that targeting the underlying orexin deficiency can improve a broad spectrum of narcolepsy type 1 symptoms, from daytime cognition to nighttime sleep architecture.
By Sree Roy
The emergence of orexin receptor 2 (OX2R) agonists represents a shift in the therapeutic approach to narcolepsy type 1 (NT1). These investigational compounds are designed to replace the signaling of the orexin neuropeptides (also known as hypocretin) that are lost in patients with NT1. By targeting the underlying cause of the disease, researchers are now evaluating whether a single intervention can address the full 24-hour cycle of the disorder.
“While excessive daytime sleepiness and cataplexy are the most recognized symptoms, many people experience additional bothersome symptoms such as cognitive difficulties and disrupted nighttime sleep,” says Emmanuel Mignot, MD, PhD, principal investigator for Takeda’s FirstLight phase 3 study, in a release. At SLEEP 2026, new data from the pivotal phase 3 program for oveporexton (TAK-861) highlighted how this mechanistic approach may translate into clinical outcomes that move beyond relief of isolated symptoms.
24-Hour Disease Framework
The concept of NT1 as a “24-hour disease” is central to the design of Takeda’s recent clinical trials. This perspective acknowledges that the absence of orexin does not merely cause sleepiness during the day; it destabilizes the entire sleep-wake regulatory system. Elena Koundourakis, PhD, global program leader for the Takeda orexin franchise, notes that this framework was informed by extensive burden-of-illness studies that Takeda conducted globally.
“You have the excessive daytime sleepiness in the morning, cataplexy throughout the day, cognitive impairment also during the day, and then the disrupted nighttime sleep,” Koundourakis observes. “This is why it is a 24-hour disease.”
By restoring orexin signaling, researchers aimed to determine if the daytime and nighttime symptoms could be addressed simultaneously. The phase 3 program, consisting of the FirstLight and RadiantLight studies, utilized a range of objective and subjective measures to capture this holistic impact. The results presented at SLEEP 2026 suggest that restoring this signaling can lead to improvements that correlate across multiple domains of a patient’s life.
Measuring Functional Impact
To better capture the lived experience of patients, researchers utilized the Functional Impacts of Narcolepsy Instrument (FINI), which evaluates six independent domains: tiredness, cognitive functioning, cataplexy, social activities, everyday activities, and everyday responsibilities. In phase 3 trials, which included 273 participants across multiple dosing arms, oveporexton showed significant improvements compared to placebo across all six domains at week 12.
The clinical relevance of these findings is underscored by the fact that many patients reached or exceeded normative thresholds for these domains. This suggests that the treatment may allow individuals to manage daily responsibilities in a manner more consistent with healthy controls. Koundourakis explains that the development of the FINI was necessary because traditional scales often failed to capture the nuances of how NT1 disrupts social and professional life.
“We really wanted to know what bothers patients most,” Koundourakis says. “We were able to capture that patients were able to resume normal day activities, such as going to school, going to work, and having a productive life.” She notes that the data showed a correlation with productivity scores, indicating that patients were less likely to be absent from work or school when their symptoms were better managed.
Quantifying Cognitive Burden
Cognitive dysfunction has historically been difficult to measure in a clinical setting, often relying on patient self-reports. However, the oveporexton phase 3 trials integrated both objective neuropsychological tests and patient-reported measures to provide a clearer picture of cognitive performance.
Objective measures included the psychomotor vigilance test, which tracks lapses in attention, as well as tests for memory and executive function. Subjectively, the FINI cognitive function domain was used to assess how patients perceived their own mental clarity. The results showed that approximately 70% of patients receiving oveporexton reported no significant cognitive difficulties at week 12, compared to only 15% in the placebo group.
“We saw deep effects unlike what has been seen in neuroscience in the past,” Koundourakis says regarding the objective cognitive data. “But then we try to see the ‘so what?’ What does it mean for patients? We used subjective tools to see how this translates into day-to-day activities, like being able to concentrate, writing emails, or watching movies uninterrupted.”
For sleep physicians, these findings emphasize the importance of screening for cognitive symptoms during routine follow-ups. While a patient may report improved wakefulness on a traditional scale, they may still struggle with the executive function required for professional or academic success.
Restoring Nighttime Sleep Architecture
One of the most complex aspects of NT1 is the intrusion of REM sleep phenomena into wakefulness and the fragmentation of sleep at night. While many current treatments focus on promoting wakefulness, they do not necessarily normalize the underlying sleep architecture.
Exploratory endpoints from the phase 3 studies showed that oveporexton shifted the timing and pattern of REM sleep toward those seen in healthy controls. Specifically, sudden onset REM periods (SOREMPs) were reduced or shifted later.
“Shifting and normalizing the sleep architecture appears to normalize the symptoms that are so bothersome for the patients,” Koundourakis says. She points to the Narcolepsy Severity Scale-Clinical Trials (NSS-CT) as a key secondary endpoint that validated these findings. “There is a correlation between the disappearance of hallucinations and sleep paralysis with the objective improvement of the sleep architecture.”
Changing the Clinical Conversation
The availability of a treatment that addresses the underlying orexin deficiency could change how sleep specialists interact with their NT1 patients. Currently, many clinical interviews are brief and focus on the frequency of cataplexy or the level of daytime sleepiness. However, if a treatment can address a broader range of symptoms, the scope of these interviews may need to expand.
Koundourakis suggests that physicians may need to spend more time discussing the functional and social impacts of the disease. “To assess the true burden of the disease, we have to take time to go through the aspects of function and quality of life,” she says. “We hope that physicians can be helped to have those conversations, to discuss what it means for patients beyond sleeping and cataplexy.”
For sleep techs, this shift may involve looking for different markers in sleep studies. The focus may shift toward more detailed analysis of REM latency and sleep stage stability as indicators of treatment efficacy.
Path to Earlier Diagnosis
Despite advances in sleep medicine, the path to an NT1 diagnosis remains long, often taking several years—and in some documented cases, much longer—in the United States. The introduction of new mechanistic therapies may serve as a catalyst for improving diagnostic awareness among primary care physicians and other specialists.
Koundourakis notes that Takeda’s ambition extends beyond treating currently diagnosed patients. “Our ambition is to get this to every patient that might have narcolepsy type 1 but has not known it for many years,” she says. She envisions a future where increased awareness of orexin’s role in the disease leads to earlier intervention, potentially saving patients from years of lost productivity and social withdrawal.
Looking ahead, success, she says, would involve not just the availability of orexin agonists, but a fundamental change in the diagnostic timeline. “Hopefully, awareness and education after oveporexton becomes available will accelerate the diagnosis, so that in five years many more patients can receive a proper diagnosis,” Koundourakis says.
Clinical Outlook for Sleep Specialists
As oveporexton moves through the regulatory review process—with a Prescription Drug User Fee Act goal date in the third quarter of 2026—the sleep medicine community is preparing for the potential arrival of the first OX2R agonist. For clinicians, the data presented at SLEEP 2026 provides a roadmap for what to expect:
- Holistic Improvement: Look for changes not just in wakefulness, but in cognitive clarity and nighttime sleep quality.
- New Metrics: Instruments like the FINI may become more common in clinical practice to track functional outcomes.
- Objective Correlation: Improvements in patient-reported outcomes are likely to be supported by objective measures like the psychomotor vigilance test and polysomnogram sleep staging.
By focusing on the underlying orexin deficiency, the field may be moving toward a standard of care that addresses NT1 in its entirety, rather than as a collection of isolated symptoms.
“We are very grateful for the strong relationships with investigators and the patients who have stuck with this program in hopes of better treatments,” Koundourakis says. As the data continues to be analyzed, the focus remains on translating these statistical improvements into meaningful changes in the daily lives of those living with narcolepsy type 1.
