Therapeutic Indications

We aspire to develop innovative medicines that address the full spectrum of orexin dysfunction in disease areas where there is high unmet medical need.

Our initial focus is on the treatment of chronic rare diseases, with rapid expansion to other disorders to maximize the number of patients who will benefit from therapies based on orexin activation.

The loss of orexin – addressing the underlying pathology in Narcolepsy Type 1

Orexia is designing orexin receptor agonists and positive modulators that will directly address the underlying disease pathology of Narcolepsy Type 1 (NT1) by restoring orexin neurotransmission in the brain. This approach may have the potential for greater efficacy, possibly addressing a broader range of NT1 symptoms than current therapies.

Narcolepsy is a chronic neurologic disorder that affects the brain’s ability to regulate the normal sleep-wake cycle in over 3 million people worldwide. Symptoms usually start between 7-25 years of age, and diagnostic delays of 6-10 years are common. Fifty percent of patients are misdiagnosed at some point during the course of the disease.

Scientific evidence indicates that NT1 is caused by a profound loss of the neurons which produce the neurotransmitter orexin, also called hypocretin. NT1 is characterized by a diverse set of symptoms that include: excessive daytime sleepiness; sleep paralysis; hallucinations upon waking up or falling asleep; disturbed night-time sleep; and cataplexy – a sudden transient loss of muscle tone that may lead to full body collapse that is usually triggered by strong emotions.

For some individuals with NT1, related symptoms such as insomnia, weight gain, mood fluctuations, and depression can have a significant debilitating impact on their lives, as described in the 2014 FDA Report, Voice of the Patient: Narcolepsy.

Potential for orexin agonists in other sleep-wake disorders

The therapeutic potential for orexin agonists extends beyond NT1 into other rare primary hypersomnia disorders such as Narcolepsy Type 2 (NT2) and Idiopathic Hypersomnia (IH), and into a broad range of indications characterized by excessive daytime sleepiness which remain inadequately treated today.

Approximately 50% of narcolepsy patients suffer from Type 2 (NT2), which is characterized by symptoms similar to NT1 but without cataplexy. It has been reported that up to a third of individuals suffering from NT2 have a partially reduced level of orexin in cerebral spinal fluid, and some of these individuals may develop cataplexy and convert to an NT1 diagnosis. IH is also a rare hypersomnolence condition characterized by episodes of extreme sleepiness. Clinical symptoms of IH may resemble NT2, but orexin levels are not reduced in IH. High unmet need for new treatments remains in both NT2 and IH.

Although the underlying mechanisms of NT2 and IH are not yet known, recent reports support the investigation of orexin agonists as potential new treatments for both disorders. In addition, a recent report suggests there may also be the potential for use of orexin agonists in treating excessive daytime sleepiness associated with obstructive sleep apnea.

Orexin research related to other therapeutic indications

Orexia is committed to research that can lead to a better understanding of the orexin system which will help to maximize the number of patients who can benefit from therapies based on orexin activation. Based on the scientific literature, these indications may extend beyond NT1 and other sleep-wake disorders to include neurodegenerative diseases, metabolic disorders, cognitive and attention disorders, and inflammatory / immune diseases.

A potential role for orexin in neurodegenerative diseases is emerging, for example. Reduction in both orexin levels and in the number of orexin neurons in the brain has been reported in Parkinson’s disease (PD), which is a neurodegenerative disorder characterized by motor symptoms such as hypokinesia, tremor and rigidity. Sleep disorders in PD are similar to those observed in narcolepsy, and may even precede motor symptoms. Excessive daytime sleepiness, REM disorders, and sleep attacks affect 15–50% of PD patients. Non-clinical studies have recently suggested a possible neuroprotective effect of orexin, and taken together, these findings support further investigation of orexin agonists as potential new treatments for Parkinson’s disease.

Orexia also recognizes the high unmet need for new treatments in other rare diseases, and we plan to explore the potential for orexin agonists in alleviating the broadest possible scope of symptoms that might be associated with the orexin system. For example, Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Individuals with PWS may exhibit excessive daytime sleepiness, excessive appetite, and obesity, and a partial loss of orexin has been observed which may relate to the severity of both obesity and excessive daytime sleepiness.

Looking forward

In summary, further research will be required to understand the role of the orexin system in human health and disease, and to realize the full potential of orexin agonists as a new therapeutic approach to address areas of unmet medical need. If you or a loved one is concerned about narcolepsy or any of the disorders mentioned here, please consult your healthcare professional.


  • Thannickal et al. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469-74.
  • Kornum et al. (2017) Narcolepsy. Nat Rev Dis Primers 3: Article 16100.
  • American Academy of Sleep Medicine. The International Classification of Sleep Disorders, Third edition. Darien, IL: American Academy of Sleep Medicine; 2014.
  • FDA The Voice of the Patient: Narcolepsy, 2014 Report
  • Tanaka et al. (2020) Selective orexin 2 receptor agonist TAK-925 to treat narcolepsy: results of a randomized, double-blind, placebo-controlled, multiple-ascending- dose, phase 1 study in patients with narcolepsy type 2. European Sleep Research Congress, Sept 22-24 (P206).
  • Rubens et al. (2021) Safety and efficacy of TAK-925 in adults with obstructive sleep apnea who experience excessive daytime sleepiness despite adequate use of CPAP. (4278) Neurology 96 (15 Supplement)
  • Fronczek et al. (2021) The orexin/hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms; in Handbook of Clinical Neurology, Vol. 180 (3rd series) p343-358.
  • Couvineau et al (2019) Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases. Front. Endocrinol. 10:709.
  • Thannickal et al. (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 130(6):1586–1595.
  • Omokawa et al. (2016) Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome. Am. J. Med. Genet. A 170, 1181–1186.