Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy. METHODS: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687. FINDINGS: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group). INTERPRETATION: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety. FUNDING: Bioprojet.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 µg auto-injector in healthy volunteers.

AIMS: Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 µg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 µg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females. METHODS: In this exploratory open-label, single-centre study, 54 healthy volunteers aged 18-50 years received a single 500 µg adrenaline injection (Anapen auto-injector) in the thigh (antero-lateral middle third [18 males] or antero-inferior third [36 females]). Assessments included depot depth (ultrasonography), plasma adrenaline levels (liquid chromatography-tandem mass spectrometry) and heart rate (HR; ECG Holter monitor). RESULTS: Ultrasonography showed that 82.4% of normal weight males received intramuscular injections; all overweight and obese females received subcutaneous injections. Anapen injection produced rapid increases in circulating adrenaline levels and significant increases in systolic blood pressure (SBP) and HR. Second peak plasma adrenaline concentrations (Cmax2 ) were reduced, and time to Cmax2 increased in overweight and obese females compared with males with normal body mass index; area under the curve (0-240 min) (AUC(0-240) ) was increased in overweight and obese females. Obese females had reduced maximal SBP values compared with normal weight males or overweight females; overweight and obese females had markedly different HR time courses compared with normal weight males. CONCLUSION: A 500 µg adrenaline injection via Anapen produced rapid PK/PD changes in normal weight, overweight and obese subjects, irrespective of intramuscular or subcutaneous injection, and was well tolerated.

Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials.

BACKGROUND: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person). OBJECTIVE: The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy. METHODS: This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy. RESULTS: The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy. CONCLUSIONS: The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials.

BACKGROUND: Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. OBJECTIVE: Analyses evaluated the time to onset of clinical response during treatment with pitolisant. METHODS: Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo. RESULTS: The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]). CONCLUSIONS: Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS. GOV IDENTIFIER: NCT01067222 (February 2010), NCT01800045 (February 2013).

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term, placebo-controlled studies.

STUDY OBJECTIVE: To evaluate the efficacy of pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, in adult patients with high burden of narcolepsy symptoms. METHODS: Data were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week. RESULTS: The analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.3; P < 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) compared with placebo (-0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant. CONCLUSIONS: Pitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP: A Randomized Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety. RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported. INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.

Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET.

BACKGROUND AND PURPOSE: BF2.649 (pitolisant, Wakix®) is a novel histamine H3 receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 receptors by BF2.649 using PET brain imaging with the H3 receptor antagonist radioligand [11 C]GSK189254. EXPERIMENTAL APPROACH: Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in nine brain regions of interest with the two tissue-compartment model with arterial input function using a common VND across the regions. Brain receptor occupancies were calculated with the Lassen plot. KEY RESULTS: Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H3 receptors. The drug was well-tolerated, and participants experienced few adverse events. CONCLUSION AND IMPLICATIONS: The administration of pitolisant (40 mg) produces a high occupancy of H3 receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 receptors.

Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Pharmacokinetics of pitolisant in children and adolescents with narcolepsy.

OBJECTIVE: To evaluate the pharmacokinetic profile and tolerability of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist, in children and adolescents with narcolepsy. METHODS: This multicenter, open-label, single-dose study of pitolisant 17.8 mg enrolled patients aged 6 through 17 years with a diagnosis of narcolepsy. Blood samples were collected at prespecified time points for analysis of pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the serum concentration-time curve from time 0-10 h (AUC0-10h). Pharmacokinetic parameters were compared across three prespecified age groups: younger pediatric patients (aged 6 to <12 years), older pediatric patients (aged 12 to <18 years), and a historical comparison group of young adults (aged 18 to <45 years). RESULTS: Of the 25 enrolled patients, 24 were included in the pharmacokinetic analysis. Pitolisant Cmax and AUC0-10h were greater (by 52% and 73%, respectively) in the younger (n = 12) versus older (n = 12) pediatric subgroup. These parameters were lower in the young adult group (n = 13) by 51% and 48%, respectively, compared with the older pediatric patients, and by 68% and 70%, respectively, compared with the younger pediatric patients. There were six treatment-emergent adverse events: headache (three), dizziness (one), diarrhea (one), and vomiting (one). CONCLUSIONS: After single-dose administration, the exposure parameters of pitolisant were significantly greater in the younger compared with older pediatric patients with narcolepsy. Pitolisant doses up to 17.8 mg/d (in children with body weight <40 kg) or 35.6 mg/d are appropriate for further evaluation in pediatric patients. TRIAL REGISTRATION: EudraCT Number: 2013-001505-93.

Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy.

OBJECTIVES: To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. METHODS: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking ("at this moment") visual analog scale. RESULTS: In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. CONCLUSIONS: In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.

Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study.

STUDY OBJECTIVES: To asses the long-term safety and efficacy of pitolisant, an histamine H3-receptor antagonist, on narcolepsy. METHODS: This open-label, single-arm, pragmatic study, recruited adult patients with narcolepsy and Epworth Sleepiness Scale (ESS) score ≥12. After a titration period, patients were treated for up to 1 year with oral pitolisant once-a-day at up to 40 mg. Concomitant stimulants and anti-cataplectic agents were allowed. The primary endpoint was safety; secondary endpoints included ESS, cataplexy, and other diary parameters. RESULTS: Patients (n = 102, 75 with cataplexy) received pitolisant, for the first time in 73 of them. Sixty-eight patients (51 with cataplexy) completed the 12-month treatment. Common treatment-emergent adverse events were headache (11.8% of patients), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depressive symptoms (4.9%), and nausea (4.9%). Seven patients had a serious adverse effect, unrelated to pitolisant except for a possibly related miscarriage. One-third of patients stopped pitolisant, mostly (19.6%) for insufficient benefit. ESS score decreased by 4.6 ± 0.6. Two-thirds of patients completing the treatment were responders (ESS ≤ 10 or ESS decrease ≥ 3), and one third had normalized ESS (≤10). Complete and partial cataplexy, hallucinations, sleep paralysis, and sleep attacks were reduced by 76%, 65%, 54%, 63%, and 27%, respectively. Pitolisant as monotherapy (43% of patients) was better tolerated and more efficacious on ESS than on add-on, but efficacy was maintained in this last case. CONCLUSIONS: Long-term safety and efficacy of pitolisant on daytime sleepiness, cataplexy, hallucinations, and sleep paralysis is confirmed.

Occupancy of dopamine D2 and D3 receptors by a novel D3 partial agonist BP1.4979: a [11C]-(+)-PHNO PET study in humans.

There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.

Bioavailability and Cardiovascular Effects of Adrenaline Administered by Anapen Autoinjector in Healthy Volunteers.

BACKGROUND: The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability. OBJECTIVE: To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections. METHODS: This randomized, open-label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor. RESULTS: Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced. CONCLUSIONS: Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis.

Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.

BACKGROUND AND PURPOSE: We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. EXPERIMENTAL APPROACH: Nonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell-derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B-recommended assays included in vitro hERG (KV 11.1) channels, in vivo dog studies with follow-up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro-arrhythmia model. KEY RESULTS: Both sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT-liability or pro-arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late INa reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide-induced early after-depolarizations (EADs) in the ICH S7B studies. Studies in stem cell-derived human cardiomyocytes with dofetilide or E-4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell-derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies. CONCLUSIONS AND IMPLICATIONS: Our findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro-arrhythmia models when the results from CiPA studies are ambiguous.

Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. METHODS: For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. FUNDING: Bioprojet, France.

Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening.

The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds. The virtual screening was planed as a two-steps process. First, using a "scout screening" methodology, we have experimentally probed the H4R ligand binding site using a small size chemical library with very diverse structures, and identified a hit that further assist us in refining a raw 3D homology model. Second, the refined 3D model was used to conduct a widened virtual screening. This two-steps strategy proved to be very successful, both in terms of structural diversity and hit rate (23%). Moreover, the hits have high affinity for the H4R, with most potent ligands in the nanomolar range.

Synthesis and evaluation of a 2-benzothiazolylphenylmethyl ether class of histamine H4 receptor antagonists.

Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.

Exploratory Phase II Trial to Evaluate the Safety and the Antiepileptic Effect of Pitolisant (BF2.649) in Refractory Partial Seizures, Given as Adjunctive Treatment During 3 Months.

BACKGROUND: Pitolisant (BF2.649) is a nonimidazole histamine 3 receptor antagonist. In previous animal studies, it has been shown that pitolisant might be helpful in chronic seizure treatment of both partial and generalized epilepsies. The present study is a multicenter, national, pragmatic, noncomparative, open-label, exploratory phase II trial. It is the first reported study of the clinical effects of pitolisant in human epilepsy. OBJECTIVE: The goal of this trial was to explore the antiepileptic effect of 3 different doses of pitolisant (20, 30, and 40 mg once daily) in patients presenting partial seizure onset despite therapy with adequate dose of 1 to 3 appropriate antiepileptic drugs. METHODS: The study has been conducted in 6 study sites in France between 2005 and 2006. The primary end point was the proportion of responders having a seizure rate decrease by at least 50%. A larger clinical trial could be started according to the results. An interim analysis was planned in the protocol to decide if the study should be continued or not according to the efficacy and safety results. Descriptive statistics were used for the analysis. RESULTS: An initial goal of 40 patients included had been planned; 23 were finally included. Pitolisant was well tolerated and achieved a clinical response in one third of patients after 3 months of treatment. CONCLUSIONS: Despite encouraging data, there is no evidence for the efficacy of the drug for the regimen that was used, but no firm conclusions can be drawn because the number of included subject was small and the study was not placebo controlled.