Recent advances in treatment for narcolepsy

Abstract

Narcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process. Little is known about NT2 etiology and prevalence, sharing with NT1 excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Despite major advances in our understanding of the neurobiological basis of NT1, management remains nowadays only symptomatic. The main and most disabling symptom, EDS, is managed with psychostimulants, as modafinil/armodafinil, methylphenidate, or amphetamines as a third-line therapy. Narcolepsy is an active area for drug development, and new wake-promoting agents have been developed over the past years. Pitolisant, a selective histamine H3 receptor inverse agonist, has been recently approved to treat patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative with dopaminergic and noradrenergic activity will be soon a new therapeutic option to treat EDS in NT1 and NT2. Sodium oxybate, used for decades in adult patients with narcolepsy, was recently shown to be effective and safe in childhood narcolepsy. The discovery of ORX deficiency in NT1 opened new therapeutic options oriented towards ORX-based therapies, especially nonpeptide ORX receptor agonists that are currently under development. In addition, immune-based therapies administered as early as possible after disease onset could theoretically slow down or stop the destruction of ORX neurons in some selected patients. Further well-designed controlled trials are required to determine if they could really impact on the natural history of the disease. Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions.

Recently Approved and Upcoming Treatments for Narcolepsy

“…Strategies being investigated for the treatment of narcolepsy include hypocretin/orexin-based strategies, such as hypocretin/orexin receptor agonists [70,71]. For example, the hypocretin/orexin 2 receptor-selective agonist TAK-925 (administered subcutaneously) has demonstrated improved wakefulness, reduced cataplexy-like episodes and ameliorated weight gain in a mouse model of narcolepsy [72,73].…”

“…Another hypocretin/orexin 2 receptor-selective agonist, TAK-994 (administered orally), increased wakefulness and reduced cataplexy-like episodes in mouse models; TAK-994 also ameliorated fragmentation of wakefulness in these models [75,76]. Additional hypocretin/orexin-based strategies under consideration include administration of orexin peptides, neuronal transplantation, stem cells and gene therapy [71].…”

“…Immune-based therapies are a strategy of interest for NT1, based on the hypothesis that destruction of hypocretin neurons in NT1 is autoimmune mediated [71,77]. A variety of immune therapies, including corticosteroids, intravenous immunoglobulin (IVIg), plasmapheresis, alemtuzumab and rituximab have been investigated; however, data are limited to case reports or small case series and results have been variable (see reviews in Barateau and Dauvilliers [71] and Barateau et al [77]).…”

Narcolepsy in Children and Adults: A Guide to Improved Recognition, Diagnosis and Management

“…Traditional stimulants are considered second-and third-line therapies for the treatment of EDS [44]. Solriamfetol and pitolisant are newer agents, but are likely to become first-line considerations for EDS [46,47].…”

“…[45] With that said, SNRIs and SSRIs are probably the most frequently prescribed antic-cataplectics, with venlafaxine being favored. It is important to note that an abrupt withdrawal of SSRI or SNRI can lead to rebound cataplexy, which is not seen with sodium oxybate [46].…”