Breakthrough Clinical Results
Takeda announced positive topline results from two pivotal Phase 3 studies (FirstLight and RadiantLight) of oveporexton (TAK-861) in narcolepsy type 1 (NT1). Both studies met all primary and secondary endpoints, demonstrating statistically significant improvements across various symptoms at all doses. Oveporexton was generally well-tolerated. Takeda plans to submit a New Drug Application to the FDA and other global regulatory authorities in fiscal year 2025. This investigational oral orexin receptor 2 (OX2R)-selective agonist aims to address the underlying orexin deficiency causing NT1 by stimulating OX2R to promote wakefulness and reduce cataplexy.
Key Highlights
- Positive topline results from two Phase 3 studies of oveporexton in narcolepsy type 1.
- All primary and secondary endpoints met, showing statistically significant improvements across symptoms.
- Oveporexton demonstrated a generally well-tolerated safety profile.
- Takeda plans to submit a New Drug Application to the FDA in fiscal year 2025.
Incidence and Prevalence
Global Epidemiology of Narcolepsy Type 1
Prevalence and Incidence Rates
The prevalence of narcolepsy in Slovakia in 2017 was 10.47 (CI 95% 8.26-14) cases/million inhabitants, with a mean incidence rate (2000-2017) of 0.57 (CI 95% 0.4-0.74) cases/million inhabitants. In Slovakia, 61 narcoleptic patients were diagnosed from 2000 to 2017, of which 51 (84%) had narcolepsy type 1 (NT1).
The prevalence of narcolepsy with cataplexy in USA and the countries of Western Europe is from 0.05-0.067%. Interestingly, the prevalence is significantly higher in Japan and lower in Israel.
Related Sleep Disorders
For comparison, the prevalence of hypersomnia in USA is between 0.3 and 16.3%, which is close to its prevalence in Europe which is 5-16%. Idiopathic hypersomnia is a rare disease, ten times as rare as narcolepsy.
Regional Characteristics
Narcolepsy is a rare disorder in Slovakia, and from the phenotype, genetic characteristics and comorbidities the disorder does not vary from other European countries.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Narcolepsy Type 1
Shared Pathophysiology and Dopaminergic Pathways
Recent research from 2024 has proposed novel connections between narcolepsy and other neurological conditions, particularly Attention Deficit Hyperactivity Disorder (ADHD). This research theorizes that in some cases, ADHD may actually predispose individuals to developing narcolepsy and hypersomnia, suggesting previously unrecognized neurobiological links.
A key finding in this emerging research is the potential shared pathophysiology between narcolepsy and various addictions through the Reward Deficiency Syndrome (RDS). Researchers hypothesize that when narcolepsy develops on a baseline of ADHD/RDS, it creates an additional assault on the dopaminergic reward system in affected individuals.
Research Methodologies and Comparative Studies
To investigate these novel mechanisms, researchers have proposed studies using a combination of broad genetic screening and neuroimaging with and without pharmacological intervention. These studies aim to compare individuals with pure ADHD, pure narcolepsy, and the combined ADHD-narcolepsy phenotype to better understand the underlying mechanisms.
The results of these proposed studies may reveal a common pathophysiology of ADHD, narcolepsy and RDS, potentially transforming our understanding of narcolepsy's neurobiological underpinnings.
Therapeutic Implications and Interventions
If evidence supports the hypothesis of shared pathophysiology for narcolepsy with RDS (and thus its subtype ADHD), early intervention/preventative treatment amongst those with ADHD may be beneficial in preventing or managing narcolepsy. The putative dopaminergic compound KB220Z™ has been mentioned as a potential treatment approach targeting these shared mechanisms.
Additionally, a 2023 study investigated solriamfetol, a dopamine/norepinephrine reuptake inhibitor, which is approved to treat excessive daytime sleepiness associated with narcolepsy (75-150 mg/day). In participants with narcolepsy on placebo, actual task effectiveness at 2 hours post-dose was lower than modeled healthy control task effectiveness, a difference not present with solriamfetol, suggesting its efficacy in addressing cognitive aspects of narcolepsy.
Associated Conditions and Management Approaches
A 2025 publication notes that adult-onset RBD (Rapid-eye-movement sleep behavior disorder) can be associated with narcolepsy among other conditions. Management of RBD relies on systematic identification of etiologic and contributing factors, implementation of safety measures, appropriate pharmacotherapy and counseling.
The American Academy of Sleep Medicine currently recommends four agents for RBD treatment that may have implications for narcolepsy management when these conditions co-occur: clonazepam, melatonin, rivastigmine, and pramipexole. There is a recognized need for additional, well-tolerated therapies for reducing RBD symptoms, which may have implications for narcolepsy management when these conditions co-occur.
These emerging mechanisms of action and treatment approaches represent significant advances in our understanding of narcolepsy type 1 and may lead to more targeted and effective therapeutic interventions in the future.
Drug used in other indications
Oveporexton (TAK-861) Clinical Indications Beyond Narcolepsy Type 1
Based on a thorough review of the available information, there is no specific data regarding Oveporexton (TAK-861) being trialed for indications beyond Narcolepsy type 1. While orexin receptor agonists as a class are being developed for various conditions including:
- Narcolepsy with or without cataplexy
- Other disorders with excessive daytime sleepiness
- Depression with insomnia
- Anxiety
- Schizophrenia
- Eating disorders
- Substance use disorders
None of these potential indications are specifically linked to TAK-861/Oveporexton in the available information.
It's worth noting that a different orexin receptor 2-selective agonist, TAK-994, has been mentioned in relation to narcolepsy type 1 trials, but there is no specific information about TAK-861's clinical trial designs, intervention models, or treatment protocols for any indication beyond Narcolepsy type 1.