**2.3 Treatments currently being developed**

1.Pitolisant (Wakix®): as we have explained previously, this is an inverse agonist of the histamine H3 receptor (competitive H3R antagonist) that acts at presynaptic level activating histaminergic neurons (it blocks the inhibitory effect of histamine on the release of endogenous histamine and improves the release in the entire central nervous system) favouring wakefulness and also with an additive anticataplectic effect. It was designated an Orphan Medicinal Product by the European Medicines Agency in 2007 and confirmed again in 2016 [5]. It was also granted orphan drug status by the FDA in 2010. It has been approved by the European Medicines Agency (EMA) in 2016 and by the FDA in 2019 for NT1 and NT2.

Dosage: single morning dose (9–36 mg/day) orally. 4.5 mg and 18 mg tablets. In Spain it is dispensed in hospital pharmacies. The guideline approved in Europe is as follows:

1st week: the starting dose is 9 mg divided into two 4.5 mg tablets to be administered at the same time in the morning.

2nd week: increase to one 18 mg tablet or consider decreasing the dose to 4.5 mg.

3rd week: the recommended dose is 36 mg, consisting of two 18 mg tablets.

Pharmacokinetics: it is rapidly absorbed, with a maximum plasma concentration (tmax) of 3.5 h and an elimination half-life (t1/2) of approximately 10–12 hours. It is metabolised through cytochrome p450 (CYP3A4) and (CYP2D6) and eliminated in urine as inactive metabolites and 25% of the dose is excreted through exhaled air.

Safety: it has a good tolerance profile even after one year of follow-up, as well as good control of cataplexy. It should be noted that Pitolisant would be of special interest to patients with cardiovascular comorbidities. It has very low abuse potential: a study in comparison to Phentermine and a placebo in patients with a history of recreational polydrug use indicated that Pitolisant, at therapeutic and supratherapeutic doses, has a similar abuse risk to the placebo. The maximum recommended dose in moderate–severe hepatic or renal impairment is 17.8 mg and it is contraindicated in end-stage kidney disease or severe liver disease. In women of childbearing age, it is recommended that a non-hormonal method of contraception be used during treatment and 21 days after stopping treatment. Antidepressants and antihistamines (which cross the blood–brain barrier) may reduce the efficacy of Pitolisant and special caution should be exercised because of the narrow therapeutic margin when using certain treatments such as immunosuppressants.

In a clinical trial, it was observed that pitolisant did not modify the pharmacokinetic profiles of oxybate or modafinil, and oxybate showed no relevant effect on pitolisant. However, a reduction in exposure was observed with modafinil, although no dose adjustment was necessary.

Side effects: in order of frequency were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness, etc. The most serious adverse effects: abnormal weight loss and miscarriage (only 0.09%).

In the HAROSA I and II trials in patients with Obstructive Sleep Apnoea Syndrome and cardiovascular comorbidities, no changes in systolic and diastolic blood pressure and heart rate were observed [6] compared to a placebo. Supratherapeutic doses between 108 and 216 mg produce an increase in the QTc interval (10–13 ms), so caution should be exercised with those drugs that prolong QT. No ECG is required before starting treatment.

Based on our clinical experience in the Sleep Unit of the Hospital General Universitario de Castellón, below we provide the results of patients who followed the compassionate-use program prior to commercialization, to initiate treatment with pitolisant in 14 adult patients and one patient with paediatric narcolepsy who did not respond to the treatments available at that time:

8 patients diagnosed with NT1: request made on the basis of EDS, and/or persistent cataplexy.

Resistance or intolerance to available treatments (modafinil, sodium oxybate, dimethylphenidate … )

3 patients with NT2: two patients with secondary narcolepsy (Steinert's myotonic dystrophy, Devic's neuromyelitis optica) and one patient with intolerance to modafinil and/or dimethylphenidate.

2 patients with idiopathic hypersomnia: one patient who reported severe hypersomnia and another patient in whom Modafinil was contraindicated due to adverse effects.

1 patient with obstructive sleep apnoea syndrome (OSAHS) who presented residual hypersomnolence without improvement with modafinil.

A 14-year-old boy with narcolepsy without cataplexy, as first line treatment for excessive daytime sleepiness after having been treated with methylphenidate.

Currently, all patients with NT2, idiopathic hypersomnia and sleepiness secondary to (OSA) continue to be treated and the symptoms of EDS have been corrected.

Of the patients with NT1, 3 continue to be treated and the cataplexy, which was mild–moderate, has been controlled. The other 5 patients dropped out due to lack of response because they presented severe cataplexy since being diagnosed with the disease.

In Ref. to safety and adverse events (AE): 2 patients out of the 15 who started treatment with pitolisant had conciliation insomnia. One was a patient with NT2 secondary to neuromyelitis optica, who presented this symptomatology with a dose of 18 mg, which was resolved by lowering the dose to 13.5 mg. The second patient presented NT1, in treatment with sodium oxybate 5.5 grams/night associated with pitolisant 36 mg/day that reverted when the dose of pitolisant was reduced to 22.5 mg. There was no other type of AE.

2. Solriamfetol (JZP-110): a selective dopamine and noradrenaline reuptake inhibitor (with no effect on the release of other monoamines) intended to improve drowsiness (EDS) in patients with obstructive sleep apnoea or narcolepsy [7]. In 2019, the FDA approved it for narcolepsy-associated drowsiness and the EMA is currently reviewing the marketing authorisation application for this indication. At the moment, experience with Solriamfetol is limited.

Dose: range 75–150 mg/day of oral administration.

Pharmacokinetics: it is rapidly absorbed, with a maximum plasma concentration (tmax) of 2 hours and an elimination half-life (t1/2) of approximately 7 hours. It is minimally metabolised and excreted mainly in the urine as an unchanged drug. Dose adjustment is recommended in moderate and severe renal insufficiency (maximum doses 75 and 37.5 mg/day, respectively). It should not be used concomitantly with monoamine oxidase inhibitors (MAOIs), which should be discontinued 2 weeks in advance.

Adverse events: headache (11.1%), nausea (6.6%) and decreased appetite (6.8%) and less frequently dry mouth, constipation, anxiety and palpitations. It is important to note that it is not necessary to discontinue oral and hormonal contraception as is recommended for modafinil and pitolisant.

Safety: Abuse potential was assessed in patients with a history of recreational polydrug use compared to phentermine. In conclusion, they present a similar or lower risk of abuse than phentermine and have therefore received a Schedule IV designation in the United States.

Two studies have been conducted: a first 12-week, randomised, double-blind, placebo-controlled phase IIb trial to evaluate efficacy in adults with narcolepsy with or without cataplexy. And a similarly designed phase III trial of 12 weeks duration for the treatment of obstructive sleep apnoea and EDS in narcolepsy.
