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

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.

The clinical trial data is promising. Posters presented at SLEEP 2018 show a reduction in cataplexy by 60%-75% in placebo-controlled phase 2 and 3 studies and favorable safety and efficacy.

Pitolisant specifically targets the histamine-3 (H3) receptor. The compound was developed by Bioprojet, a Paris, France-based pharmaceutical company established in 1982. “The principals are Jean-Charles Schwartz and Jeanne-Marie Lecomte, both scientists,” Dayno says. “Jean-Charles Schwartz is the individual who discovered it, so it really came out of their labs. He’s spent his life working on the histaminergic system. He discovered the histamine-3 receptor and cloned it, and then started to design molecules as an H3 receptor antagonist/inverse agonist. He went through a series and then optimized the product design and came up with pitolisant.”

Bioprojet has marketed the product in Europe since its approval by the European Medicines Agency in 2016; it is known there by the trade name Wakix and is dosed as a once daily tablet. In October 2017, Harmony Biosciences, via its parent incubator-investor Chicago-based Paragon Biosciences, acquired the exclusive US right to develop, register, and market the drug.

Pitolisant has two complementary mechanisms of action on histamine. It is a highly-selective H3 receptor antagonist and also an H3 receptor inverse agonist. By acting on presynaptic histamine H3 receptors, pitolisant as an antagonist blocks the binding of histamine to the receptor, releasing the virtual brake that would otherwise be in place, and so allows more histamine to come out of the presynaptic neuron. The inverse agonist quality means it up- or down-regulates histamine depending on how much activity is going on. Together, they increase histaminergnic transmission in the brain. “It’s very potent and very selective for the histamine-3 receptor,” Dayno says.

If Harmony Biosciences earns FDA approval for pitolisant, then healthcare professionals can expect to see histamine take a starring role in treating other rare conditions as well. “It’s almost a pipeline product opportunity because there are other potential clinical applications down the road,” Dayno says. “Our main focus now is preparing for the NDA and submitting that….But we’ve already been approached with some very interesting follow-on clinical development opportunities mediated through the H3 receptor.”

Sree Roy is editor of Sleep Review.