**3. Summary**

In recent years there has been a significant increase in new therapeutic options such as Pitolisant and Solriamfetol, aimed at developing better control of narcolepsy symptoms.

Pitolisant is positioned as a first-line drug of choice for the management of symptoms such as excessive daytime sleepiness and cataplexy, in addition to being able to be used in both adults and children, and is the only one of the new therapeutic lines whose use is considered in paediatric narcolepsy. With regard to the usual treatments, as we have already mentioned, a clinical trial with sodium oxybate in the paediatric population has also been published recently.

Solriamfetol would be included in the first line treatment of excessive daytime sleepiness (EDS) in adults. In addition, the use of both Pitolisant and Solriamfetol would be advisable as a first-line strategy, in combination with the other anticataplectic drugs for a better control of cataplexy. Both can be used in combination for second-line treatment of EDS.

Pharmacological strategy of the European guidelines for the treatment of narcolepsy [8]:

## *Sleep Medicine and the Evolution of Contemporary Sleep Pharmacotherapy*

#### **3.1 Therapies under development**

1.AXS-12 (Reboxetine): a selective NA reuptake inhibitor with a weak effect on 5-HT reuptake and no effect on DA reuptake. It is a drug initially intended for the treatment of depression. It is currently in development for the treatment of cataplexy and EDS associated with narcolepsy. The FDA has designated it as an orphan drug. Preclinical data have shown a reduction in cataplexy and sleep attacks in narcoleptic mice (attributed to an effect on NA reuptake inhibition). Since noradrenaline reuptake inhibitors are very effective for the treatment of cataplexy, it will probably be used to control cataplexy and become an alternative for patients who cannot take oxybate and pitolisant. One of the possible indications could be the treatment of patients with major depressive disorder and narcolepsy [8].

Pharmacokinetics: Rapidly absorbed after oral administration (tmax) approximately 2–4 h and eliminated mainly through metabolism by CYP3A4.

Safety: A Phase II, randomised, double-blind, placebo-controlled, crossover study is underway in participants with narcolepsy with cataplexy and EDS.

Adverse events: dry mouth, hyperhidrosis, constipation and restlessness were reported in a 2-week pilot study. Post-marketing experience (with indication for depression) has reported other AEs such as: insomnia, dizziness, dry mouth, constipation, nausea and hyperhidrosis.

2.THN102 (modafinil/flecainide): this is the association of the inhibitory effect of astroglial connexins associated with a dopamine reuptake inhibitor, improving the coupling of astroglial cells, since it is believed that astrocytes and astroglial connexins are involved in the regulation of sleep and wakefulness. In the cortex, modafinil would act by increasing the expression of messenger RNA (mRNA) and the connexin 30 protein, one of the main astroglial connections. On the other hand, flecainide has an inhibitory effect on astroglial connexins. In preclinical studies, flecainide enhanced the

#### *Narcolepsy Treatment: Present and Future DOI: http://dx.doi.org/10.5772/intechopen.99777*

procognitive and wakefulness-promoting effects of modafinil in mice and modafinil/flecainide coadministration decreased the number and duration of direct transitions to REM sleep in orexin-inactivated mice.

Pharmacokinetics: not specifically reported. Data from mouse models indicate that flecainide did not affect the pharmacokinetic parameters and bioavailability of modafinil.

Efficacy: evaluated in a three-way, phase II, double-blind, randomised, placebo-controlled, crossover trial in 48 adults with narcolepsy with or without cataplexy for 2 weeks. Participants received modafinil/flecainide 300/ 3 mg, modafinil/flecainide 300/27 mg and modafinil 300 mg/placebo in each of the three periods. Preliminary results indicated no difference in efficacy between THN102 and modafinil alone. This could be due to an overrepresentation of participants with severe narcolepsy who presented a low response to modafinil.

Safety: no safety data currently available.

The potential role of THN102 in narcolepsy is unclear. The narcolepsy study was stopped due to lack of efficacy in the phase II study.


Dosage: 4.5–6-7.5 or 9 g once a night.

Pharmacokinetics: A Phase III trial evaluating the bioavailability of FT218 compared to immediate-release sodium oxybate (Xyrem®) in healthy volunteers is currently under development.

Efficacy: of FT218 is being evaluated in another phase III, multi-centre, double-blind, placebo-controlled REST-ON trial (Randomised study Evaluating the efficacy and SafeTy of a Once Nightly formulation of sodium oxybate). Adverse effects are expected to be similar to immediate-release sodium oxybate.

5. JZP-258: is a new low sodium oxybate product (combination of sodium oxybate, potassium oxybate, calcium oxybate and magnesium oxybate) and has 92% less sodium. It would therefore be more advisable for use in patients with hypertension, heart failure or renal failure). In addition, it is tolerated better because it does not leave an unpleasant taste and does not have as many gastrointestinal effects as sodium oxybate.

Pharmacokinetics: lower Cmax, longer tmax and similar AUC were obtained compared to sodium oxybate.

Efficacy: evaluated in a phase III multi-centre, randomised, phase III withdrawal study.

Adverse events: reported most frequently were headache (22.4%), nausea (13.4%) and dizziness (11.4%); treatment-related SAEs were reported in only two participants. In addition, a 24-week open-label safety study is underway.

6. SUVN-G3031: is an inverse agonist of the histamine 3 receptor (H3R) that is in phase II development.

Anticataplectic and wakefulness-promoting effects have been observed in rodents, increasing acetylcholine, histamine, DA and NA levels in the cortex, but without altering DA levels in the striatum or nucleus accumbens, which might suggest a lower abuse potential. No adverse effects on ECG parameters, fertility, embryofoetal development or CNS safety concerns have been reported in preclinical studies.

7.TAK-925: is a selective agonist of the hypocretin/orexin 2 receptor (ORX2R). It has demonstrated wakefulness-promoting effects in wild mice and primates. It also increased wakefulness time and improved wakefulness fragmentation and cataplexy and attenuated weight gain in ORX/ataxin-3 transgenic mice without changing food intake. If the results are confirmed, it could be targeted to treat a wide range of symptoms without causing ORX2R desensitisation.

Pharmacokinetics: A Phase I study with single ascending doses (7–240 mg, administered as an intravenous infusion over 9 hours) has been conducted in 36 healthy volunteers, evaluating safety, pharmacokinetics and tolerability. In addition, another placebo-controlled crossover study was carried out in 14 NT1 patients where doses of (5, 11.2 and 44.8 mg, as a 9 h intravenous infusion) were administered [9]. The exposure was proportional to the dose over the dose range studied and t1/2 was less than 2 h; PKs were similar in healthy volunteers and NT1 patients.

Adverse events: increase in blood pressure and HR. Improved mean sleep latency as determined by the TMW maintenance of wakefulness test in NT1 patients (from 22.4, 37.6, and 40.0 min with TAK-925 5, 11.2, and 44.8 mg, respectively, compared to 2.9 min with placebo.

8.TAK-994a selective hypocretin/orexin 2 receptor agonist (administered orally), has been shown to increase wakefulness and reduce cataplexy-like episodes in mouse models and to improve wakefulness fragmentation in these models.
