A rare disorder of the central nervous system, narcolepsy blurs the boundary between sleeping and waking. It causes excessive daytime sleepiness and irresistible bouts of sleep that can last a few seconds to several minutes. Sudden loss of muscle control (known as cataplexy), sleep paralysis, fragmented sleep, and hallucinations are also common. Yet despite this list of debilitating symptoms, narcolepsy often goes undiagnosed or misdiagnosed for years. When patients do finally get a proper diagnosis—on average seven years [checking this number] after initial onset of symptoms—they are discouraged by the limited therapeutic options available to them.

In the US, treatment for this incurable disease consists of a combination of behavioral modifications (naps and consistent bedtimes) and medications aimed at mitigating only some of the symptoms, with side effects that can make them intolerable. No approved therapies address the underlying causes of the disease.

The first step is to understand the molecular nature of the disorder. Over the last decade [ck] researchers discovered that the most common form of narcolepsy is caused by the destruction, often in childhood, of a group of neurons in the hypothalamus that secrete small awakening peptides called hypocretins. Acting as a neurotransmitter, hypocretins plays a major role in the maintenance of wakefulness during the day, mainly by activating other wake-promoting neurons called histaminergic neurons, which release histamine. In narcolepsy, the lack of hypocretin-producing neurons is partly compensated for by an increase in the number of histamine neurons, but this is not enough to maintain wakefulness and prevent the occurrence of dangerous cataplexy attacks.

Our partners, Bioprojet researchers Dr. Jeanne-Marie Lecomte and Dr. Jean-Charles Schwartz, began investigating the potential of targeting the body’s natural histamine braking system to see if they could activate the release of more brain histamine, thereby boosting wakefulness in narcolepsy patients. They learned that these brakes—auto-receptors called histamine 3, or H3—could indeed be blocked by a small molecule that binds to it.  No one understands this receptor better than Dr. Swartz: he discovered H3 more than 50 years ago, and he and Dr. Lecomte have spent years figuring out how it works, whether it can be controlled, and what molecules can change it’s behavior.

After TK years of development, our partners created pitolisant, a first-in-class drug that acts as a highly selective H3-receptor inverse agonist/antagonist. In 2016, the drug was approved in Europe for the treatment of narcolepsy in adults with or without cataplexy, but it is not yet approved in the United States. Harmony intends to establish an expanded access program (EAP) for pitolisant in the US in early 2018 and expect to submit a new drug application (NDA) for the treatment of narcolepsy in adult patients during the first half of 2018.

While pitolisant for the treatment of narcolepsy and cataplexy are the initial focus of our clinical development program, we believe there is tremendous potential in the H3 receptor beyond narcolepsy. Harmony and Bioprojet will continue collaborative research and development under the guidance of a joint development committee. We are both proud and excited to be a part of the prospective novel treatments it might offer for a range of CNS disorders and we look forward to applying rational drug development strategies to solve these patient challenges.


In clinical trials conducted in patients with narcolepsy, the most frequent adverse drug reactions (ADRs) reported with pitolisant were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%), fatigue (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), weight increase (0.9%), and upper abdominal pain (0.9%). Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C) and in women breastfeeding their children.