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

NeurologyLiveAugust 2020
Volume 3
Issue 4

Managing narcolepsy via behavioral strategies to improve excessive daytime sleepiness may be challenging but has shown some added efficacy when combined with pharmacological treatment for EDS.

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


1. Kornum BR, Knudsen S, Ollila HM, et al. Narcolepsy. Nat Rev Dis Primer. 2017;3:16100. doi:10.1038/nrdp.2016.100

2. BaHammam AS, Alnakshabandi K, Pandi-Perumal SR. Neuropsychiatric correlates of narcolepsy. Curr Psychiatry Rep. 2020;22(8):36. doi:10.1007/s11920-020-01159-y

3. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6(9):991-997. doi:10.1038/79690

4. Faraco J, Mignot E. Immunological and genetic aspects of narcolepsy. Sleep Med Res. 2011;2(2):39-47. doi:10.17241/smr.2011.2.2.39

5. Valko PO, Gavrilov YV, Yamamoto M, et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol. 2013;74(6):794-804. doi:10.1002/ana.24019

6. Panula P, Chazot PL, Cowart M, et al. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine receptors. Pharmacol Rev. 2015;67(3):601-655. doi:10.1124/pr.114.010249

7. Monti JM. Involvement of histamine in the control of the waking state. Life Sci. 1993;53(17):1331-1338. doi:10.1016/0024-3205(93)90592-Q

8. Lovenberg TW, Roland BL, Wilson SJ, et al. Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol. 1999;55(6):1101-1107. doi:10.1124/mol.55.6.1101

9. Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology. 2016;106:56-73. doi:10.1016/j.neuropharm.2015.11.005

10. Shi Z, Fultz RS, Engevik MA, et al. Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis. Am J Physiol Gastrointest Liver Physiol. 2019;316(1):G205-G216. doi:10.1152/ajpgi.00212.2018

11. Sadek B, Saad A, Sadeq A, Jalal F, Stark H. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behav Brain Res. 2016;312:415-430. doi:10.1016/j.bbr.2016.06.051

12. Berlin M, Boyce CW, Ruiz M de L. Histamine H3 receptor as a drug discovery target. J Med Chem. 2011;54(1):26-53. doi:10.1021/jm100064d

13. Morisset S, Rouleau A, Ligneau X, et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature. 2000;408(6814):860-864. doi:10.1038/35048583

14. Barbier AJ, Bradbury MJ. Histaminergic control of sleep-wake cycles: recent therapeutic advances for sleep and wake disorders. CNS Neurol Disord Drug Targets. 2007;6(1):31-43. doi:10.2174/187152707779940790

15. Hancock AA. The challenge of drug discovery of a GPCR target: analysis of preclinical pharmacology of histamine H3 antagonists/inverse agonists. Biochem Pharmacol. 2006;71(8):1103-1113. doi:10.1016/j.bcp.2005.10.033

16. Lin JS. Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med Rev. 2000;4(5):471-503. doi:10.1053/smrv.2000.0116

17. Lin JS, Dauvilliers Y, Arnulf I, et al. An inverse agonist of the histamine H3 receptor improves wakefulness in narcolepsy: studies in orexin−/− mice and patients. Neurobiol Dis. 2008;30(1):74-83. doi:10.1016/j.nbd.2007.12.003

18. Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. The European Medicines Agency Review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use. Sleep Med. 2017;33:125-129. doi: 10.1016/j.sleep.2017.01.002

19. Harmony Biosciences announces FDA approval of WAKIX (pitolisant), a first-in-class medication for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. News release. Harmony Biosciences. August 15, 2019. Accessed June 5, 2020.

20. Lamb YN. Pitolisant: a review in narcolepsy with or without cataplexy. CNS Drugs. 2020;34(2):207-218. doi:10.1007/s40263-020-00703-x

21. Szakacs Z, Dauvilliers Y, Mikhaylov V, et al; HARMONY-CTP Study Group. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200-207. doi:10.1016/S1474-4422(16)30333-7

22. Dauvilliers Y, Bassetti C, Lammers GJ, et al; HARMONY I Study Group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12(11):1068-1075. doi:10.1016/S1474-4422(13)70225-4

23. Li S, Yang J. Pitolisant for treating patients with narcolepsy. Expert Rev Clin Pharmacol. 2020;13(2):79-84. doi:10.1080/17512433.2020.1714435

24. Harmony Biosciences presents 5-year data on pitolisant at international narcolepsy symposium. News release. Harmony Biosciences. September 11, 2018. Accessed June 5, 2020.

25. Guo RX, Anaclet C, Roberts JC, et al. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice. Br J Pharmacol. 2009;157(1):104-117. doi:10.1111/j.1476-5381.2009.00205.x

26. Effectiveness of the drug GSK189254 in treating patients with narcolepsy. Updated March 10, 2017. Accessed July 22, 2020.

27. Barbier AJ, Berridge C, Dugovic C, et al. Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br J Pharmacol. 2004;143(5):649-661. doi:10.1038/sj.bjp.0705964

28. Benade V, Daripelli S, Tirumalasetty C, et al. 0054 SUVN-G3031, a histamine H3 receptor inverse agonist produces wake promoting effect in orexin-2-saporin lesioned rats. Sleep. 2019;42(suppl 1):A22-A23. doi:10.1093/sleep/zsz067.053

29. Nirogi R, Mudigonda K, Bhyrapuneni G, et al. Safety, tolerability, and pharmacokinetics of SUVN-G3031, a novel histamine-3 receptor inverse agonist for the treatment of narcolepsy, in healthy human subjects following single and multiple oral doses. Clin Drug Investig. 2020;40:603-615. doi:10.1007/s40261-020-00920-8

Related Videos
Ana Krieger, MD, MPH
 Jocelyn Y. Cheng, MD
Mark I. Boulos, MD, BSc, FRCP, CSCN, MSc
© 2024 MJH Life Sciences

All rights reserved.