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A Biopharma Company Explains Why Histamine Matters in Narcolepsy

Hypocretin (orexin) isn't the only neurotransmitter that contributes to sleep-wake state stability, says Harmony Biosciences' chief medical officer.

SLEEP REVIEW MAGAZINE, June 12, 2018 — By Sree Roy

Narcolepsy is a disorder of sleep-wake state instability. Too-rapid transitions from one state to another result in its signature symptoms, such as cataplexy and hypnagogic hallucinations—examples of wake and sleep states intermingling.

For people with type 1 narcolepsy (previously dubbed narcolepsy with cataplexy), the instability is linked to low levels of hypocretin, also known as orexin—a neurotransmitter produced in the hypothalamus that plays a leading role in promoting wakefulness and regulating rapid eye movement (REM) sleep.

But one biopharmaceutical company is working on a US Food and Drug Administration (FDA) new drug application (NDA) for a narcolepsy treatment that targets histamine, not hypocretin. In the role of regulating sleep-wake states, histamine could be considered the overlooked understudy to hypocretin. Both neurotransmitters are produced in the deep brain region of the hypothalamus and both go to other neurotransmitters that drive wakefulness, as well as to the REM neuron centers, according to Harmony Biosciences, LLC chief medical officer Jeffrey Dayno, MD. Harmony Biosciences recently earned "Breakthrough Therapy" and "Fast Track" designations from the FDA for this investigational product, named pitolisant, and presented several abstracts on the compound at SLEEP 2018.

"We think histamine, along with hypocretin, is another major neurotransmitter that contributes to sleep-wake state stability. In narcolepsy, especially type 1 (with cataplexy) when you have diminished hypocretin, we think that driving the histaminergic system—the way pitolisant is working—is compensating for the loss of hypocretin and helping to stabilize the system," Dayno says.

The outflow of histamine is from the tuberomammillary nucleus (TMN) in the hypothalamus, which is in close physical proximity to the outflow of hypocretin, Dayno explains. Though people with narcolepsy don't have a histamine deficiency, increasing histaminergic transmission in the brain can still improve sleep-wake state instability. "Theoretically, in the normal physiologic state of sleep-wake stability, hypocretin—with its outflow to the TMN (where histamine is) and to other neurotransmitters that drive wakefulness (norepinephrine, serotonin, dopamine, as well as others)—creates that stability between sleep and wake.

"Histamine is upstream and histamine projections also go to similar projections that hypocretin goes to: It goes to the other neurotransmitters that drive wakefulness. It goes to dopamine, norepinephrine, serotonin. It goes to the REM neuron centers as well. In a deficient state, we think it may fill in to help bring the system back to help with sleep-wake state stability," Dayno says.