Wakix (pitolisant) / Bioprojet, Ferrer International, Paragon Biosci, RareStone Group, Aculys Pharma - LARVOL DELTA

Efficacy and Safety of Pitolisant for Excessive Daytime Sleepiness in Narcolepsy and Obstructive Sleep Apnea: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Ann Pharmacother) - "Pitolisant significantly improves subjective and objective wakefulness and quality of life in EDS due to narcolepsy or OSA, with robust evidence for ESS benefit and a favorable safety profile."

Journal • Retrospective data • Review • CNS Disorders • Excessive Daytime Sleepiness • Excessive Daytime Sleepiness in Narcolepsy • Insomnia • Mood Disorders • Narcolepsy • Obstructive Sleep Apnea • Pain • Pediatrics • Psychiatry • Respiratory Diseases • Sleep Disorder

Reciprocal regulation of the H 3 histamine receptor in Rett syndrome and MECP2 Duplication syndrome: implications for therapeutic development. (PubMed, bioRxiv) - "We evaluated both a small molecule agonist of the H 3 receptor, ( R )-α-methylhistamine (RAMH), and pitolisant in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT ( Mecp Null/+ ), but pitolisant had no effect on the behaviors examined here in MDS animals ( MECP2 Tg1 )."

Journal • Developmental Disorders • Mood Disorders • Movement Disorders • Narcolepsy • Psychiatry • Sleep Disorder

...Harmony is on track to submit a New Drug Application (NDA) for pitolisant GR in early 2026, targeting a PDUFA date in Q1 2027. (Businesswire)

FDA approval • FDA filing • Narcolepsy

Improvement of hypersomnia symptoms and development of novel hypersomnia therapeutics focusing on the histamine-metabolizing enzyme HNMT. (Neuroscience 2025) - "For example, histamine H3 receptor inverse agonists—such as pitolisant, an approved treatment for narcolepsy—regulate histamine release...Several promising compounds have been identified and are currently undergoing counter-assays to confirm their specificity. Additionally, we are using crystal structure analysis to further characterize select candidates.These findings underscore the therapeutic promise of HNMT inhibition for hypersomnia and emphasize the importance of developing next-generation inhibitors with enhanced specificity and brain penetrance."

Cataplexy • CNS Disorders • Movement Disorders • Narcolepsy • Parkinson's Disease • Sleep Disorder

State-dependent noradrenaline release in the ventrolateral preoptic area of narcoleptic mice (Neuroscience 2025) - "These findings indicate that lower NA tone in the VLPO may contribute to the excessive daytime sleepiness of narcolepsy. In addition, pitolisant increases NA levels in the VLPO, and inhibition of sleep-promoting VLPO neurons may contribute to its wake-promoting effects."

Preclinical • Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder • GAL

The effect of pitolisant on neurons of the ventrolateral preoptic area (Neuroscience 2025) - "These results suggest that, in addition to direct activation of wake-promoting regions, pitolisant also promotes arousal by inhibiting sleep-promoting neurons in the VLPO. Pitolisant's actions in the VLPO involve activation of local GABAergic circuits via H3 receptors plus and the release of NA, both of which contribute to the inhibition of VLPOGal neurons."

CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder • GAL

Comparative efficacy of new wake-promoting agents for narcolepsy-a network meta-analysis. (PubMed, BMC Neurol) - "All of the approved new wake-promoting drugs are effective in controlling narcolepsy symptoms with acceptable adverse effects. Trial Registration The study was prospectively registered in the INPLASY database (INPLASY2024120052)."

Journal • Retrospective data • Review • Cataplexy • CNS Disorders • Mood Disorders • Narcolepsy • Psychiatry • Sleep Disorder

Unlocking Value: Assessing the Cost-Effectiveness of Pitolisant Wakix®in Portugal (ISPOR-EU 2025) - "The results suggest a favourable cost-effectiveness profile especially considering th high burden of disease burden and that no therapeutic alternatives are available. While uncertainty remains due to limited local epidemiological data, expert input and sensitivity analyses help mitigate it. This study presents a new model and highlights the need to generate and integrate local data into health technology assessments."

Cost effectiveness • HEOR • Cataplexy • Narcolepsy • Sleep Disorder

PHARMACOLOGIC VS NONPHARMACOLOGIC INTERVENTION IN THE MANAGEMENT OF EXCESSIVE DAYTIME SLEEPINESS IN OBSTRUCTIVE SLEEP APNEA (CHEST 2025) - "Other pharmacologic treatments, including armodafinil, pitolisant, and solriamfetol, have demonstrated efficacy in improving wakefulness, particularly in patients with residual sleepiness. Excessive daytime sleepiness (EDS) is a major concern in obstructive sleep apnea (OSA), especially for those with persistent symptoms despite CPAP therapy. While CPAP remains the gold standard, other interventions offer potential benefits. Treatment options like carbocysteine and herbal remedies have shown promise in reducing EDS, though more research is needed."

Excessive Daytime Sleepiness • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Effect of sleep apnoea interventions on multiple health outcomes: an umbrella review of meta-analyses of randomised controlled trials. (PubMed, EClinicalMedicine) - "CPAP, wake stimulants, HNS, and myofunctional therapy significantly reduced daytime sleepiness (ESS score SMDs of -0.80 to -0.88; moderate-certainty evidence except for pitolisant and solriamfetol, which were supported by high-certainty evidence). Data need to be interpreted in the context of several limitations, including those relating to the meta-analysis inclusion criteria and the quality of data in the meta-analyses themselves. None."

HEOR • Journal • Cognitive Disorders • Obstructive Sleep Apnea • Pediatrics • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Long-Term Efficacy and Safety of Pitolisant for Residual Sleepiness Due to OSA (CHEST 2025) - No abstract available

Clinical • Obstructive Sleep Apnea

2252: Practice-Changing Research in Sleep, Presented by CHEST ® Journal (CHEST 2025) - "3. Building on recent clinical trials showing the efficacy of pitolisant for short-term treatment of daytime sleepiness, take a deep dive into a recent clinical trial investigating the long-term effectiveness and safety of the medication."

CNS Disorders • Human Immunodeficiency Virus • Infectious Disease • Obstructive Sleep Apnea • Sleep Disorder

AN ASSESSMENT OF THE EDUCATIONAL NEEDS OF PULMONOLOGISTS AND OTHER HEALTH CARE PROVIDERS IN THE UNITED STATES ON THE MANAGEMENT OF PATIENTS WITH NARCOLEPSY (CHEST 2025) - "Clinicians' initial medication recommendations for a diagnosis of NT1 varied; most would start with a nonamphetamine stimulant (47% of pulmonologists and 55%–70% of other clinicians), and few pulmonologists recommended sodium oxybate or pitolisant (46% combined)...Clinicians reported only moderate satisfaction with currently available treatment options for patients with narcolepsy, and they had limited familiarity with emerging treatment options, such as the orexin receptor 2–selective agonist TAK-861... This survey provides evidence that clinicians who manage patients with sleep disorders, including pulmonologists, have educational needs in narcolepsy and orexin sleep science. CLINICAL IMPLICATIONS: Specific educational topics relevant to clinicians who manage patients with sleep disorders include the diagnostic approach and treatment of narcolepsy, emerging treatments for narcolepsy, and orexin biology."

Clinical • Cataplexy • Depression • Excessive Daytime Sleepiness • Mood Disorders • Narcolepsy • Sleep Disorder

A Study of Pitolisant in Participants With Prader-Willi Syndrome (clinicaltrials.gov) - P3 | N=150 | Enrolling by invitation | Sponsor: Harmony Biosciences Management, Inc.

New P3 trial • Prader–Willi syndrome

Targeting Oligodendrocyte Dysfunction in Alzheimer's Disease: a New Frontier for Drug Repurposing with Antihistamines and Serotonin Receptor Agonists. (PubMed, J Mol Neurosci) - "We discuss pharmacological strategies to correct OL dysfunction by drug repurposing: first-generation H1-antihistamine clemastine, which induces OPC maturation by M1 muscarinic antagonism and ERK/mTOR signalling; H3-receptor antagonists/inverse agonists (e.g. pitolisant) increase neurotransmitter release and induce CREB-mediated remyelination; and serotonergic GPCR agonists (5-HT4, 5-HT6, 5-HT2C) shift APP processing toward non-amyloidogenic pathways, enhance synaptic proteostasis, and protect OLs against 5-HT toxicity. We present a clinical translation roadmap featuring adaptive, biomarker-responsive trials that utilise enhanced myelin imaging; personalised and multi-omics approaches to medicine; and transdisciplinary collaboration among neuroscience, pharmacology, regulatory bodies, and patient-caregiver groups. The translation of repurposed glial-targeting therapies to clinical practice will require adaptive, biomarker-guided trials, advanced myelin imaging, and..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation • Solid Tumor

Drug Interactions With Excessive Daytime Sleepiness Treatments. (PubMed, J Pharm Technol) - "Objective: To evaluate the potential for drug interactions with pharmacotherapy for central hypersomnolence (modafinil, armodafinil, solriamfetol, pitolisant, sodium oxybate, methylphenidate, amphetamine, lithium, clarithromycin). Available literature indicates that pharmacotherapy for central hypersomnolence is associated with clinically significant drug interventions and subsequent possible adverse reactions. Clinicians in all practice settings should be mindful of the potential to minimize drug interactions and optimize pharmacotherapy for hypersomnolence."

Journal • Review • Excessive Daytime Sleepiness • Sleep Disorder

Proof of Concept Study on Pitolisant Effect on Autism Spectrum Disorders in Children and Adolescents (clinicaltrials.gov) - P2 | N=62 | Active, not recruiting | Sponsor: Bioprojet | Recruiting ➔ Active, not recruiting

Enrollment closed • Autism Spectrum Disorder • Genetic Disorders

Understanding idiopathic hypersomnia: diagnosis, pathophysiology, and management. (PubMed, Curr Opin Pulm Med) - "Growing insights into the pathophysiology and clinical features of idiopathic hypersomnia have led to improved diagnostic clarity and therapeutic innovation. These developments carry significant implications for clinical practice, offering hope for better symptom control and quality of life in affected individuals. Ongoing research is crucial for refining treatment strategies and deepening our understanding of this complex condition."

Journal • Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder

Treatment of residual excessive daytime sleepiness (rEDS) in OSA Patients: A Real-Life Monocentric Experience (ERS 2025) - "Pitolisant significantly reduces rEDS and depression without affecting sleep quality. Although fatigue reduction was observed, statistical significance was not reached, possibly due to sample heterogeneity. These findings support that Pitolisant can improve quality of life."

Clinical • Depression • Excessive Daytime Sleepiness • Fatigue • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Pitolisant in the Management of Obstructive Sleep Apnea with Persistent Daytime Sleepiness Despite CPAP/APAP Adherence: A Retrospective Observational Study (ERS 2025) - "The treatment was discontinued in 2(1 due to insomnia and the other at the patient's request). No cardiovascular events were observed Patients treated with pitolisant showed a reduction in excessive daytime sleepiness No significant cardiovascular side effects were observed during pitolisant treatment."

Adherence • Observational data • Retrospective data • Cardiovascular • Excessive Daytime Sleepiness • Insomnia • Narcolepsy • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Effect of sleep apnoea interventions on multiple health outcomes: umbrella review of meta-analyses of randomised controlled trials (ERS 2025) - "CPAP and wakefulness-promoting agents (solriamfetol, pitolisant, modafinil) effectively reduced daytime sleepiness. BP reduction was most significant with CPAP combined with diet/lifestyle changes. Knowledge gaps persist regarding non-CPAP therapies, adherence, and combination treatments, which likely represent the future of personalized OSA management."

Clinical • HEOR • Review • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder

Pitolisant may lessen not only sleepiness but improve hyperphagia and behavior problems in Prader-Willi Syndrome. (PubMed, J Clin Sleep Med) - No abstract available

Journal • Prader–Willi syndrome

Hormonal Contraceptive and Pitolisant CYP3A4 Induction (WSS 2025) - "Introduction: Some narcolepsy treatments (e.g. modafinil) are contraindicated in narcoleptic patients taking oral contraceptives as they reduce their plasma levels by inducing CYP3A4...In the traditional one the metabolism of midazolam was evaluated... Pitolisant at therapeutic dose is devoid of any inducer activity on CYP3A4 and, therefore, represents a valuable alternative for treating Excessive Daytime Sleepiness and cataplexy in female patients with narcolepsy taking hormonal contraceptive drugs"

Cataplexy • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder • CYP3A4

Primary Efficacy and Safety Results of a Phase 2, Double-Blind, Placebo-Controlled, Proof-of-Concept, Signal Detection Study of Pitolisant in Myotonic Dystrophy (WSS 2025) - "Pitolisant reduced EDS in adults with DM1 in a dose-dependent manner. The safety and tolerability profile of pitolisant in patients with DM1 was consistent with the known safety profile of pitolisant."

Clinical • P2 data • Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Fatigue • Genetic Disorders • Insomnia • Muscular Dystrophy • Myotonic Dystrophy • Narcolepsy • Pediatrics • Sleep Disorder

Pitolisant for Excessive Daytime Sleepiness in Prader-Willi Syndrome: Phase 2 Study Results and Phase 3 Clinical Trial Design (WSS 2025) - P3 | "In a phase 2 proof-of-concept study, pitolisant reduced EDS in patients with PWS. Pitolisant may also reduce behavioral disturbances and hyperphagia. The ongoing phase 3 clinical trial is further evaluating the efficacy and safety of pitolisant in a larger population of patients ≥6 years old with PWS and EDS."

Clinical • P2 data • P3 data • Cataplexy • Excessive Daytime Sleepiness • Genetic Disorders • Mental Retardation • Mood Disorders • Narcolepsy • Pediatrics • Prader–Willi syndrome • Psychiatry • Sleep Disorder