The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use

Kollb-Sielecka, Marta; Démolis, Pierre; Emmerich, Joseph; Markey, Greg; Salmonson, Tomas; Haas, Manuel

doi:10.1016/j.sleep.2017.01.002

Cited by 234 publications

(50 citation statements)

References 9 publications

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“…The pitolisant development program in narcolepsy was characterized by eight Phase II/III studies (P07-03 and P09-15, respectively, Harmony I and Harmony Ibis were pivotal studies). In addition, two studies, P11-05 (Harmony CTP)43 and P09-10 (Harmony III), were supportive for the evaluation by EMA 44. Key characteristics of the study designs and a summary of the main results are reported in Table 1.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 93%

“…The efficacy of pitolisant in treating narcolepsy was demonstrated in two main, double-blind, 8-week, multicenter, parallel-group, placebo-controlled randomized trials 44. Each of these used a flexible dosing schedule.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

“…The second pivotal RCT, Harmony Ibis44 evaluated narcoleptic patients randomly allocated to pitolisant (n=67), modafinil (n=65), or placebo (n=33). The drug regimen involved increasing the pitolisant and modafinil doses: 3 weeks of flexible dosing according to clinical symptoms (10 and 20 mg/day of pitolisant; 100, 200, 400 mg/day of modafinil) followed by 5 weeks of stable dosage.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

“…P09-10 (Harmony III) was a Phase III, open-label, prospective, longitudinal, uncontrolled, multicenter trial designed to evaluate the long-term safety of pitolisant in the treatment of EDS in narcolepsy 44. The study enrolled 102 adult narcoleptic patients with or without cataplexy who had completed a double-blind controlled study with pitolisant (Harmony I, the prematurely stopped Harmony II, Harmony Ibis, or other Phase II studies in narcolepsy), patients who would be unable to participate in a double-blind study but could benefit from pitolisant, or patients receiving pitolisant under the French compassionate use program.…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

“…Safety was assessed mainly from data obtained in narcolepsy studies, but also from RCTs in different clinical contexts (Parkinson’s disease and sleep apnea related to EDS, epilepsy, dementia, attention-deficit/hyperactivity disorder, schizophrenia) 44. At this moment, the clinical program for pitolisant involves 1,385 subjects (291 healthy controls and 1,094 patients, of whom 342 were suffering from narcolepsy, while the remaining 742 patients were being treated for different indications).…”

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

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Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Romigi

Vitrani

Giudice

et al. 2018

DDDT

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Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep dysregulation, manifesting as cataplexy and sleep paralysis, as well as hypnagogic and hypnopompic hallucinations. Disease onset may occur at any age, although adolescents and young adults are mainly affected. Currently, the diagnosis delay ranges from 8 to 10 years and drug therapy may only attenuate symptoms. Pitolisant is a first-in-class new drug currently authorized by the European Medicines Agency to treat narcolepsy with or without cataplexy in adults and with an expanded evaluation for the treatment of neurologic diseases such as Parkinson’s disease and epilepsy. This article reviews the pharmacokinetic and pharmacodynamic profile of pitolisant, highlighting its effectiveness and safety in patients with narcolepsy. We performed a systematic review of the literature using PubMed, Embase, and Google Scholar. We report on the efficacy and safety data of pitolisant in narcoleptic patients regarding cataplexy episodes and subjective and objective daytime sleepiness. The development program of pitolisant was characterized by eight Phase II/III studies. One proof-of-concept study followed by two pivotal studies, three randomized controlled trials, and two open studies were evaluated. Our review confirmed the effectiveness of pitolisant in treating major clinically relevant narcolepsy symptoms, including cataplexy, as compared to placebo. In addition, pitolisant revealed a safe profile when compared with placebo and active comparators. Headache, insomnia, and nausea were the prominent side effects. Further long-term randomized controlled trials comparing the efficacy of pitolisant with active comparators (ie, modafinil and sodium oxybate) may clarify its real place in therapy and its possible use as a first-line agent on the basis of its safety and tolerability.

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Section: Pitolisant: Design and Developmentmentioning

confidence: 93%

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

Section: Pitolisant: Design and Developmentmentioning

confidence: 99%

See 3 more Smart Citations

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Romigi

Vitrani

Giudice

et al. 2018

DDDT

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A randomized study of solriamfetol for excessive sleepiness in narcolepsy

Thorpy

Shapiro

Mayer³

et al. 2019

Annals of Neurology

285

121

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Objective Solriamfetol (JZP‐110) is a selective dopamine and norepinephrine reuptake inhibitor with wake‐promoting effects. This phase 3 study (NCT02348593) evaluated the safety and efficacy of solriamfetol in narcolepsy. Methods Patients with narcolepsy with mean sleep latency <25 minutes on the Maintenance of Wakefulness Test (MWT), Epworth Sleepiness Scale (ESS) score ≥10, and usual nightly sleep ≥6 hours were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Coprimary endpoints were change from baseline to week 12 in MWT and ESS. Improvement on the Patient Global Impression of Change (PGI‐C) was the key secondary endpoint. Results Safety and modified intention‐to‐treat populations included 236 and 231 patients, respectively. Solriamfetol 300 and 150 mg were positive on both coprimary endpoints. Least squares mean (standard error [SE]) changes from baseline were 12.3 (SE = 1.4) and 9.8 (SE = 1.3) minutes for solriamfetol 300 and 150 mg on the MWT, respectively, versus 2.1 (SE = 1.3) minutes for placebo, and −6.4 (SE = 0.7) for 300 mg and −5.4 (SE = 0.7) for 150 mg on the ESS versus −1.6 (SE = 0.7) for placebo (all p < 0.0001). At week 12, higher percentages of patients treated with solriamfetol 150 mg (78.2%) and 300 mg (84.7%) reported PGI‐C improvement relative to placebo (39.7%; both p < 0.0001). Adverse events ≥5% across all solriamfetol doses included headache (21.5%), nausea (10.7%), decreased appetite (10.7%), nasopharyngitis (9.0%), dry mouth (7.3%), and anxiety (5.1%). Interpretation Solriamfetol has the potential to be an important therapeutic option for the treatment of impaired wakefulness and excessive sleepiness in patients with narcolepsy. ANN NEUROL 2019;85:359–370.

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A Photoswitchable Agonist for the Histamine H₃ Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor

et al. 2019

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Spatiotemporal control over biochemical signaling processes involving G protein‐coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H3 receptor (hH3R). Upon illumination, key compound 65 decreases its affinity for the hH3R by 8.5‐fold and its potency in hH3R‐mediated Gi protein activation by over 20‐fold, with the trans and cis isomer both acting as full agonist. In real‐time two‐electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light‐induced modulation of hH3R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.

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The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use

Cited by 234 publications

References 9 publications

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

A randomized study of solriamfetol for excessive sleepiness in narcolepsy

A Photoswitchable Agonist for the Histamine H₃ Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor

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The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use

Cited by 234 publications

References 9 publications

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy

A randomized study of solriamfetol for excessive sleepiness in narcolepsy

A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor

Contact Info

Product

Resources

About

A Photoswitchable Agonist for the Histamine H₃ Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor