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

Development and validation of a method for quantitative determination of the genotoxic impurity diethyl sulfate in pitolisant hydrochloride via high-performance liquid chromatography. (PubMed, RSC Adv) - "The method demonstrated an LOD and LOQ of 4 ppm and 12 ppm, respectively. This developed HPLC methodology proved to be well-suited for quantifying trace levels of the potential genotoxic impurity diethyl sulfate (DES) in pitolisant hydrochloride, a by-product originating from the synthesis process."

Journal

Harmony Biosciences Reports Strong Q1 2025 Financial Results, Highlights Advancement of Its Pipeline and Upcoming Catalysts, and Reaffirms 2025 Revenue Guidance ​ (Businesswire) - "WAKIX (pitolisant) Net Revenue of $184.7 Million for First Quarter 2025; Representing 20% Growth Year-over-Year....On track to initiate Phase 3 registrational trials in both narcolepsy and IH in Q4 2025 with potential PDUFA dates in 2028....Pitolisant GR (gastro-resistant): Topline data readout anticipated in Q3 2025 with potential PDUFA date in 2026. Orexin-2 receptor agonist (BP1.15205): Comprehensive preclinical safety and efficacy data to be presented at SLEEP 2025 (June)....IMPD submission on track for mid-2025; first-in-human study expected to initiate 2H 2025 with clinical data anticipated in 2026."

Clinical data • FDA approval • New trial • Sales • Narcolepsy • Sleep Wake Cycle Disorder

Efficacy and Safety of Pitolisant in Residual Excessive Daytime Sleepiness for Patients With Obstructive Sleep Apnea Adhering to Continuous Positive Airway Pressure Therapy: An Individual Patient Meta-Analytical Approach (ATS 2025) - "Pitolisant 20 mg and 40 mg were significantly therapeutically superior to placebo in treating residual EDS in patients with OSA who received CPAP on the outcomes for ESS, OSLER, and QoL."

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

Acute hypobaric hypoxia attenuates the anti-fatigue effects of pitolisant by downregulating the expression of organic cation transporter 1 and P-glycoprotein. (PubMed, Front Pharmacol) - "Pitolisant shows potential for supporting circadian rhythm regulation in shift workers and individuals suffering from jet lag. When used under HH conditions, adjusting the dose and frequency may be necessary due to altered pharmacokinetics."

Journal • Fatigue • SLC22A1

Characteristics of Patients Enrolled in a Pharmacist Managed Rare Disease Program: Highlighting National Diversity and Representation (ISPOR 2025) - "Program engagement metrics included duration of enrollment and number of completed assessments. Among the 7,633 patients enrolled in the Ph-RDP, 55% were diagnosed with sleep disorders, primarily treated with pitolisant, while 34% had sickle cell disease, with voxelotor being the most common medication. The findings highlight the program's broad reach, including substantial patient enrollment from rural and urban areas and high vulnerability areas as a proxy for providing accessible care to underserved populations. Patient participation and high engagement levels, evidenced by the number of assessments and duration of enrollment, emphasize the program's potential impact in improving care and health outcomes."

Clinical • CNS Disorders • Genetic Disorders • Hematological Disorders • Rare Diseases • Sickle Cell Disease • Sleep Disorder

Safety and Efficacy of Pitolisant on Excessive Daytime Sleepiness and Other Non-Muscular Symptoms in Patients With Myotonic Dystrophy Type 1 (clinicaltrials.gov) - P2 | N=30 | Completed | Sponsor: Harmony Biosciences Management, Inc. | Active, not recruiting ➔ Completed

Trial completion • Excessive Daytime Sleepiness • Genetic Disorders • Muscular Dystrophy • Myotonic Dystrophy • Sleep Disorder

Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Residual Sleepiness in Obstructive Sleep Apnea Despite Continuous Positive Airway Pressure: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. (PubMed, CNS Drugs) - "Among all WPAs, solriamfetol demonstrated the highest efficacy on ESS and MWT, with the latter being significant. Modafinil demonstrated the best clinician impression, albeit not statistically significant. All four WPAs were associated with a low risk of serious or adverse events."

Journal • Retrospective data • Review • CNS Disorders • Depression • Mood Disorders • Obstructive Sleep Apnea • Psychiatry • Respiratory Diseases • Sleep Disorder

Pitolisant alleviates brain network dysfunction and cognitive deficits in a mouse model of Alzheimer's disease. (PubMed, Transl Psychiatry) - "Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Narcolepsy • Sleep Disorder

Expert consensus on the diagnosis and treatment of excessive daytime sleepiness in obstructive sleep apnea (PubMed, Zhonghua Jie He He Hu Xi Za Zhi) - "Surgical interventions can also be used as an adjunctive therapy to CPAP (2, B).Recommendation 6: OSA patients with EDS should make lifestyle changes, including correcting poor lifestyle habits and improving sleep hygiene, to improve nocturnal sleep quality and daytime alertness (3, B).Recommendation 7: Pharmacological wake-promoting agents may be considered, after careful clinical evaluation, in OSA patients who meet the following criteria: ① Residual EDS persists despite adequate and adherent conventional OSA therapy (including CPAP, oral appliances, and surgery) with exclusion of other EDS etiologies; ② Patients with EDS who refuse, are intolerant of, or are not compliant with conventional therapy; ③ Patients with EDS that severely impairs quality of life, interferes with work/study performance, or increases the risk of accidents (including those with actual or near-miss accidents) (expert consensus, ungraded).Recommendation 8: For patients with residual EDS despite..."

Journal • Cardiovascular • CNS Disorders • Excessive Daytime Sleepiness • Obstructive Sleep Apnea • Psychiatry • Respiratory Diseases • Sleep Disorder

Personalized endpoints in Prader-Willi syndrome: a case study with goal attainment scaling. (PubMed, J Clin Sleep Med) - "This case report examines the implementation of Goal Attainment Scaling (GAS) for a 9-year-old girl with Prader-Willi Syndrome (PWS) and narcolepsy-like features who began treatment with Pitolisant, a medication designed to alleviate excessive daytime sleepiness...This method provided an unbiased assessment of treatment effectiveness, underscoring the importance of integrating patient-centered measures in the management of rare diseases like PWS. The findings suggest that GAS can yield valuable insights into patient priorities and treatment outcomes, highlighting the need for further research into its application in clinical settings for PWS and similar conditions."

Journal • Excessive Daytime Sleepiness • Narcolepsy • Prader–Willi syndrome • Rare Diseases • Sleep Disorder

Management options for excessive daytime sleepiness in patients with obstructive sleep apnea. (PubMed, Expert Rev Respir Med) - "Solriamfetol and pitolisant are wake-promoting agents (WPA) recently approved for use in sleepy OSA patients accepting or refusing OSA treatment...However, it is still uncertain which subgroups of patients should be treated for the symptom of EDS while maintaining a low-risk profile in terms of consequences of OSA on health. Until such data are available, use of WPA in OSA patients should be managed by Sleep Specialists."

Journal • Review • Cardiovascular • Excessive Daytime Sleepiness • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

Narcolepsy & Idiopathic Hypersomnia Patient Journey, Clinical Features and Treatments in a Real-World US Population (AAN 2025) - "Common treatments included SSRI/SNRI (57%), stimulants (41%), and wake-promoting agents (39%); 15% of NT1 patients received oxybate and 2.6% pitolisant...In a large real-world US population, sleep diagnostic evaluations were underutilized and many patients were untreated. A small proportion received narcolepsy-specific medications. These results indicate an unmet need for effective diagnostic and treatment strategies for patients with narcolepsy/IH."

Clinical • Real-world • Real-world evidence • Cardiovascular • CNS Disorders • Depression • Genetic Disorders • Mood Disorders • Narcolepsy • Obesity • Obstructive Sleep Apnea • Psychiatry • Respiratory Diseases • Sleep Apnea • Sleep Disorder • Substance Abuse

Franchise Highlights (Businesswire) - "Pitolisant HD (high-dose)...Phase 3 registrational trial in narcolepsy to include endpoint on narcolepsy-related fatigue in pursuit of differentiated label: Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028; Phase 3 registrational trial in IH to include endpoint on sleep inertia in pursuit of differentiated label: Trial to initiate in Q4 2025; topline data readout anticipated in 2027 with potential PDUFA date in 2028; Provisional IP filed out to 2044 for narcolepsy and IH....Pitolisant GR (gastro-resistant): Pivotal bioequivalence study on track to initiate Q1 2025: Topline data readout anticipated in Q3 2025 with potential PDUFA in 2026; Provisional IP filed out to 2044."

Clinical data • FDA approval • New P3 trial • Patent expiry • Narcolepsy • Sleep Wake Cycle Disorder

WAKIX in Narcolepsy (Businesswire) - "Net Sales were $201.3M for Q4 2024 and $714.7M for FY 2024; 2025 Net Revenue projected between $820 to $860 million; Settlement reached in first Abbreviated New Drug Application (ANDA) litigation, giving Novugen Pharma a license to sell its generic product beginning in January 2030 or earlier under certain circumstances; This settlement reinforces the strength and durability of Harmony’s intellectual property portfolio and its vigorous defense of its patent estate; On track to obtain pediatric exclusivity which, if granted, would add an additional 6 months of regulatory exclusivity."

Generic launch • Patent • Sales • Narcolepsy

Interim analysis of a post-authorization safety study of pitolisant in treating narcolepsy: A real-world European study. (PubMed, Sleep Med) - "Pitolisant was generally safe and well tolerated in patients with NT1 and NT2 and can be used in both types. Improvements were found in EDS, cataplexy, and quality of life, with good adherence and satisfaction."

Journal • Real-world evidence • Cardiovascular • Cataplexy • CNS Disorders • Excessive Daytime Sleepiness • Genetic Disorders • Narcolepsy • Obesity • Psychiatry • Sleep Disorder

Harmony Biosciences Provides Update on the Status of the Supplemental New Drug Application for Pitolisant in Idiopathic Hypersomnia (Businesswire) - "Harmony Biosciences Holdings, Inc...today announced that it received a Refusal to File (RTF) letter from the U.S. Food and Drug Administration (FDA) for pitolisant for the treatment of excessive daytime sleepiness (EDS) in adult patients with idiopathic hypersomnia (IH)...'We are on track to initiate a Phase 3 registrational trial of Pitolisant HD in IH in Q4 2025, with a target PDUFA date in 2028.'"

FDA event • New P3 trial • PDUFA • Excessive Daytime Sleepiness • Sleep Disorder

Efficacy and safety of pitolisant in residual excessive daytime sleepiness for patients with obstructive sleep apnea adhering to continuous positive airway pressure therapy in the HAROSA studies: An individual patient meta-analytical approach. (PubMed, Sleep Med) - "Pitolisant 20 mg and 40 mg were significantly therapeutically superior to placebo in treating residual EDS in patients with OSA who received CPAP on the outcomes for ESS, OSLER, and QoL."

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

Harmony Biosciences Reports Strong 2024 Revenues, Provides 2025 Revenue Guidance and Highlights Key Pipeline Catalysts (Businesswire) - "Q1 – FDA decision on file acceptance of pitolisant sNDA for Idiopathic Hypersomnia (IH); IH sNDA for pitolisant submitted in Q4 2024; Potential FDA approval in 2025..."

FDA approval • FDA filing • Sleep Disorder

Armodafinil as Monotherapy in Treating Narcolepsy with Cataplexy. (PubMed, Cureus) - "In narcolepsy with cataplexy, sodium oxybate and the recently FDA-approved drug pitolisant are preferred medications. Armodafinil, a longer-acting, non-amphetamine stimulant, is often used in patients who have narcolepsy without cataplexy...It is known that sodium oxybate, through its gamma-aminobutyric acid type B (GABA-B) receptor agonist activity, helps in cataplexy and EDS. However, in some instances, like this patient, armodafinil alone improves the symptoms of cataplexy and maintains wakefulness."

Journal • Monotherapy • Cataplexy • Excessive Daytime Sleepiness • Narcolepsy • Sleep Disorder

Trends and variation in issuance of high-cost narcolepsy drugs by NHS England organisations and regions from 2019 to 2022. (PubMed, J Sleep Res) - "Volumes were converted to World Health Organisation defined daily doses, to estimate the monthly number of defined daily doses of sodium oxybate, pitolisant and solriamfetol issued by each integrated care board and region. Variations between integrated care boards and regions differ substantially by drug and route of issuance. Our findings describe substantial variation in the use of specialist narcolepsy drugs in England, and highlight the untapped potential of using large, public domain datasets to publicly review higher-cost drug prescribing."

Journal • Narcolepsy • Sleep Disorder

Histamine H3 receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization during resting state: an exploratory cortex-wide imaging study in mice. (PubMed, Mol Brain) - "Graph theory analysis revealed increases in centrality measures in the somatosensory cortex with the use of both thioperamide and pitolisant, indicative of their importance in the organization of cortical networks. These findings indicate that H3 receptor inverse agonists/antagonists influence intra-regional cortical activity and inter-regional synchronization of activity in the cerebral cortex during the resting state."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry

First Report on Cationic Triphenylphosphonium Compounds as Mitochondriotropic H3R Ligands with Antioxidant Properties. (PubMed, Antioxidants (Basel)) - "Compound 6e showed the highest affinity (Ki H3R = 14.1 nM), comparable to that of pitolisant...On the other hand, cytotoxic effects in SH-SY5Y neuroblastoma cells were investigated using the colorimetric alamar blue assay, which revealed significant effects on cell viability with an unequivocally structure-toxicity relationship. Finally, docking and molecular simulation studies were used to determine the H3R binding form, which will allow us to further modify the compounds to establish a robust structure-activity relationship and find a lead compound with therapeutic utility in neurodegenerative diseases."

Journal • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Evaluation of pitolisant, sodium oxybate, solriamfetol, and modafinil for the management of narcolepsy: a retrospective analysis of the FAERS database. (PubMed, Front Pharmacol) - "However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy."

Journal • Retrospective data • CNS Disorders • Cognitive Disorders • Depression • Developmental Disorders • Immunology • Mental Retardation • Movement Disorders • Narcolepsy • Obstructive Sleep Apnea • Psychiatry • Respiratory Diseases • Restless Legs Syndrome • Sleep Apnea • Sleep Disorder • Suicidal Ideation

Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy. (PubMed, Sleep) - "In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain, and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy."

Journal • Preclinical • Cataplexy • Mood Disorders • Narcolepsy • Psychiatry • Sleep Disorder

Comorbidity of obstructive sleep apnea and narcolepsy: A challenging diagnosis and complex management. (PubMed, Sleep Med X) - "No studies were found concerning the treatment of EDS in double-diagnosis patients, but only case reports; these latter and the experience on patients with either NT or OSA suggest that modafinil, methylphenidate, pitolisant and solriamfetol are effective. The association with OSA is likely to be explained by the involvement of orexin in hypercapnic-hypoxic responses: a deficit of orexin may promote obstructive events during sleep. Open questions warrant further investigation, especially orexin's involvement in other sleep disorders associated with EDS, and the more appropriate treatment for the OSA-narcolepsy comorbidity."

Journal • Review • CNS Disorders • Excessive Daytime Sleepiness • Narcolepsy • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder