Selective Inverse Agonists of the Histamine 3 Receptor as Treatment for Narcolepsy

Narcolepsy is a chronic sleep disorder of autoimmune origin that affects roughly 1 in 2000 to 4000 individuals, occurring in men and women but with some variability in prevalence among racial and ethnic groups.¹ It is characterized by excessive daytime sleepiness (EDS), sleep paralysis, hallucinations while falling asleep or waking, and, in some cases, sudden loss of muscle tone triggered by strong emotion (cataplexy), all symptoms that can seriously diminish quality of life.¹ Comorbid neuropsychiatric manifestations in patients with narcolepsy (eg, eating disorders, depression, anxiety, and psychosis) often impair early diagnosis due to shared common features.² To date, there are no treatments that hinder or slow disease development, but lifestyle changes and support groups have helped patients cope with narcolepsy. Medications that suppress sleepiness can also assist with managing symptoms, but careful selection and supervision are required due to the potent adverse effects (AEs) and addiction potential of most prescribed stimulants.¹

Managing narcolepsy via behavioral strategies (eg, implementing good sleep hygiene and seeking counseling) to improve EDS may be challenging but has shown some added efficacy when combined with pharmacological treatment for EDS.¹ Current treatments for narcolepsy symptoms include classic central nervous system (CNS) stimulants (eg, modafinil, amphetamines, sodium oxybate, and caffeine) to treat EDS and antidepressants (eg, fluoxetine, venlafaxine, or clomipramine) to treat cataplexy.¹ These drug therapies may be costly and are sometimes associated with harmful AEs, including dependency; therefore, a need exists for narcolepsy treatments with improved safety and efficacy.

Narcolepsy is a chronic neurological condition affecting neurons in the hypothalamus that produce hypocretins 1 and 2 (also called orexins A and B, respectively),¹ which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2 Genetic analysis of individuals with narcolepsy has shown that lack of the peptide neurotransmitter hypocretin, a hallmark of this disease, is generally not caused by mutations in hypocretin-encoding genes. Instead, the approximately 70,000 hypothalamic neurons that produce hypocretin are lost in a process that is poorly understood but remarkably specific, sparing adjacent neurons that express melanin-concentrating hormone.^3,4 This deficit in hypocretin neurons cannot be compensated for simply by administration of hypocretins because of their poor bioavailability. However, patients with narcolepsy have a documented 94% increase in the number of histaminergic neurons within the hypothalamic tuberomammillary nucleus; over time, this may compensate for the loss of hypocretin signaling.⁵ In fact, the brain histaminergic system controls several essential physiological functions, including arousal and maintenance of wakefulness.⁶ For these reasons, the histaminergic system has gained interest in narcolepsy research.

Histamine, also known as the “waking amine,”⁷ mediates its effects through binding to 4 known G protein—coupled receptor subtypes, H1R to H4R. H4R, which remains poorly understood, shares high homology with H3R but not with H1R and H2R.^8,9 H1R, H2R, and H4R expression is described in immune cells, hepatocytes, and endothelial cells, where they mediate slow excitatory postsynaptic potentials.^9,10 H3R, on the other hand, is predominantly expressed in the CNS, where it functions as a presynaptic autoreceptor to negatively regulate histamine synthesis and release,^10,11 as well as a heteroreceptor to control the release of other neurotransmitters, such as acetylcholine, in various brain regions.¹² Modulation of cortical activity and the sleep-wake cycle could therefore be achieved via H3R and its ligands.

Such histamine receptor ligands can be classified as agonists, neutral antagonists, or inverse agonists: agonists are ligands with a lower affinity for receptors in the uncoupled state, whereas the affinity of neutral antagonists is unaffected by the coupling state, and inverse agonists have a higher affinity for the uncoupled state of the receptor.¹¹ Of significance to narcolepsy therapeutics and the treatment of brain disorders (eg, Alzheimer disease and schizophrenia) are inverse agonists of H3R; it is especially important to suppress the relatively high constitutive activity of H3R.¹¹ Inverse agonists of H3R work by enhancing the release of histamine, which then competes with the ligand for occupancy of autoreceptors, thus inhibiting the constitutive activity of H3R and stabilizing it in the inactive state (FIGURE).¹³

H3R inverse agonists have had success in therapeutic management of behavioral deficiencies associated with schizophrenia in mouse models,^9,11 supporting the development of H3R inverse agonists to treat EDS and cataplexy. Classic H3R inverse agonists have been shown to increase wakefulness and to decrease sleep in rodent and feline models,¹⁴ although the effects are compound- and species-dependent.¹⁵ For example, the imidazole H3R inverse agonists thioperamide and ciproxifan promote cortical activation and waking, whereas the H3R agonists α-methylhistamine, imetit, and BP2-94 enhance cortical slow activity and increase slow-wave sleep.¹⁶ Based on these robust effects in animal sleep-wake control, H3R ligands were investigated for treatment of human sleep-wake disorders, with the hope that these ligands would be H3R specific, modulate only histamine neurotransmission, and promote effects on sleep-wake parameters that are comparable or even stronger than those of classic psycho-stimulants. Most chemical series currently under investigation are nonimidazole in nature, which provides advantages of being more selective for H3R versus H1R, H2R, or H4R, and increasing CNS penetration while minimizing drug-drug interactions.¹⁵

Pitolisant (Wakix; Harmony Biosciences) is a potent, orally available, once-daily, first-in-class, wake-promoting selective inverse agonist of H3R with a good preclinical and clinical benefit to risk ratio for the treatment of narcolepsy.¹⁷ It was approved in the European Union in March 2016 for the treatment of narcolepsy with or without cataplexy in adults,¹⁸ and United States approval was granted in August 2019 for the treatment of EDS in adults with narcolepsy.¹⁹ Pitolisant functions by activating not only histaminergic and noradrenergic neurons but also the wake-promoting cholinergic and dopaminergic neurons.¹⁷ Results from pivotal, supportive phase 3 trials (HARMONY I, NCT01067222; HARMONY 1bis, NCT01638403) suggested that a dose of up to 40 mg per day for adults was significantly superior to placebo for enhancing wakefulness and decreasing cataplexy rate, although pitolisant was comparable to modafinil in management of EDS.²⁰

Pitolisant was demonstrated to have minimal risk of abuse in preclinical and clinical studies, and it remains the only antinarcoleptic drug not scheduled as a controlled substance in the United States.²⁰ In the HARMONY CTP (NCT01800045) and HARMONY I (NCT01067222) trials, no patients on pitolisant experienced amphetamine-like withdrawal syndrome during the withdrawal phase, whereas this AE occurred in several patients treated with modafinil.^21,22 Patients taking pitolisant also did not experience hypersomnia or fatigue upon treatment interruption, and Beck Depression Inventory scores improved significantly from baseline compared with placebo (P = .02).²¹ Blood chemistry and hematological and cardiovascular parameters were consistent with those of controls.²¹ Overall, pitolisant was well tolerated in clinical trials, with participants typically experiencing few AEs, primarily headache, insomnia, nausea, and anxiety, which are consistent with its mechanism of action.^20,23 Long-term safety data for pitolisant in individuals with narcolepsy are currently limited to the HARMONY III trial in adults (NCT01399606),²⁴ with a complementary prolonged open-label study ongoing in pediatric patients (NCT02611687).

Other H3R inverse agonists have been evaluated in clinical trials for treatment of narcolepsy. The efficacy of GSK189254 was similar to that of modafinil in terms of increased wakefulness, reduced slow-wave sleep, and decreased paradoxical sleep in mice,²⁵ although a phase 2 clinical trial (NCT00366080) was terminated based on the interim results of a futility test.²⁶ A phase 2 study (NCT00424931) of a new formulation of modafinil, JNJ-17216498, was conducted based on promising preclinical data for a related compound, JNJ-5207852, which demonstrated increased wakefulness and a favorable pharma- cokinetic profile in mice.²⁷ Although the clinical trial was completed in 2007, no additional information has been released since 2014. Preclinical data for SUVN-G3031 showed increased wakefulness in a rat model of narcolepsy.²⁸ In 2 phase 1 clinical studies (NCT02342041 and NCT02881294), single doses up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy human subjects, with no effects of age, sex, or fasting status on the agent’s pharmacokinetics and safety profile.²⁹ An ongoing phase 2 study evaluating SUVN-G3031 safety and efficacy in patients with narcolepsy began in September 2019 (NCT04072380).

In conclusion, narcolepsy is a condition of sleepiness for which life-long treatment is likely to be required. Promising advances involve using novel agents to treat targeted symptoms such as EDS, with the potential to treat more than 1 symptom of narcolepsy. However, cost, convenience, and AEs remain challenges. Furthermore, although the beneficial effects of pitolisant in EDS and cataplexy treatment are well substantiated, the use of H3R inverse agonists in cognitive disorders is promising but requires further testing.References

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