Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX11.

Mechanism of action
Pitolisant is a potent, orally active histamine H3-receptor antagonist/inverse agonist which, via its blockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a major arousal system with widespread projections to the whole brain. Pitolisant also modulates various neurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain.

However, no increase in dopamine release in the striatal complex including nucleus accumbens was evidenced for pitolisant.

Narcolepsy with or without cataplexy

Pharmacodynamic effects
In narcoleptic patients with or without cataplexy, pitolisant improves the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT)) and attention (e.g. Sustained Attention to Response Task (SART)).

Clinical efficacy and safety

Narcolepsy (with or without cataplexy) is a chronic condition. The effectiveness of pitolisant up to 36 mg once a day, for the treatment of narcolepsy with or without cataplexy was established in two main, 8 weeks, multicenter, randomized, double-blind, placebo-controlled, parallel group trials (Harmony I and Harmony CTP). Harmony Ibis, study with a similar design, was limited to 18 mg once a day. Long-term safety data of Wakix in this indication are available in the open label long-term study HARMONY III.

The pivotal study (Harmony 1), double-blind, randomized, vs placebo and modafinil (400 mg/day), parallel group studies with flexible dose adaptation, included 94 patients (31 patients treated with pitolisant, 30 with placebo and 33 with modafinil). Dosage was initiated at 9 mg once a day and was increased, according to efficacy response and tolerance to 18 mg or 36 mg once a day per 1-week interval. Most patients (60%) reached the 36 mg once a day dosage. To assess the efficacy of pitolisant 
on Excessive Daytime Sleepiness (EDS), Epworth Sleepiness Scale (ESS) score was used as primary efficacy criterion. The results with pitolisant were significantly superior to those in the placebo group (mean difference: -3.33; 95%CI [-5.83 to -0.83]; p < 0.05) but did not differ significantly from the results in the modafinil group (mean difference: 0.12; 95%CI [-2.5 to 2.7]). The waking effect of the two active substances was established at similar rates (Figure 1).

Figure 1: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline to week 8 in Harmony 1 study



The effect on Epworth was supported in two laboratory tests of vigilance and attention (Maintenance of Wakefulness Test (MWT) (p=0.044) and Sustained Attention to Response (SART) (p=0.053, almost but not significant)).

Cataplexy attacks frequency in patients displaying this symptom was decreased significantly (p=0.034) with pitolisant (-65%) compared to placebo (-10%). The daily cataplexy rate (geometric means) was 0.52 at baseline and 0.18 at final visit for pitolisant and 0.43 at baseline and 0.39 at final visit for placebo, with a rate ratio rR=0.38 [0.16 ; 0.93] (p=0.034).

The second pivotal study (Harmony Ibis) included 165 patients (67 treated with pitolisant, 33 with placebo and 65 with modafinil). The study design was similar to study Harmony I except that the maximum dose for pitolisant reached by 75% of patients was 18 mg once a day instead of 36 mg in Harmony I. As an important unbalance led to comparison of results with or without cluster grouping of sites, the most conservative approach showed non-significant ESS score decrease with pitolisant compared to placebo (pitolisant-placebo=-1.94 with p=0.065). Results from cataplexy rate at 18 mg once a day were not consistent with those of the first pivotal study (36 mg once a day).

Improvement of the two objective tests of wakefulness and attention, MWT and SART, with pitolisant was significant versus placebo (p=0.009 and p=0.002 respectively) and non-significant versus modafinil (p=0.713 and p=0.294 respectively).

Harmony CTP, a supportive double blind, randomized, parallel group study of pitolisant versus placebo, was designed to establish pitolisant efficacy in patients with high frequency cataplexy in narcolepsy. The primary efficacy endpoint was the change in the average number of cataplexy attacks per week between the 2 weeks of baseline and the 4 weeks of stable treatment period at the end of study. 105 narcoleptic patients with high frequency weekly cataplexy rates at baseline were included (54 patients treated with pitolisant and 51 with placebo). Dosage was initiated at 4.5 mg once a day 

and was increased, according to efficacy response and tolerance to 9 mg, 18 mg or 36 mg once a day per 1-week interval. Most patients (65%) reached the 36 mg once a day dosage.

On the primary efficacy endpoint, Weekly Rate of Cataplexy episodes (WRC), the results with pitolisant were significantly superior to those in the placebo group (p < 0.0001), with a progressive 64% decrease from baseline to end of treatment (Figure 2). At baseline, the geometric mean of WRC was 7.31 (median=6.5 [4.5; 12]) and 9.15 (median=8.5 [5.5; 15.5]) in the placebo and pitolisant groups respectively. During the stable period (until the end of treatment), geometric mean WRC decreased to 6.79 (median=6 [3; 15]) and 3.28 (median=3 [1.3; 6]) in the placebo and pitolisant groups respectively in patients who had experienced at least one episode of cataplexy. The observed WRC in pitolisant group was about half of WRC in the placebo group: the effect size of pitolisant compared with placebo was summarized by the ratio rate rR(Pt/Pb), rR=0.512; 95%CI [0.435 to 0.603]; p < 0.0001). The effect size of pitolisant compared with placebo based on a model for WRC based on BOCF with centre as a fixed effect was 0.581, 95%CI [0.493 to 0.686]; p<0.0001.

Figure 2: Changes in weekly cataplexy episodes (geometric mean) from Baseline to week 7 in Harmony CTP study



*p<0.0001 vs placebo

The effect of pitolisant on EDS was also assessed in this population using the ESS score. In the pitolisant group, ESS decreased significantly between baseline and the end of treatment compared to placebo with an observed mean change of -1.9 ± 4.3 and -5.4 ± 4.3 (mean ± sd) for placebo and pitolisant respectively, (p<0.0001) (Figure 3). This effect on EDS was confirmed by the results on Maintenance of Wakefulness Test (MWT). The geometric mean of the ratios (MWTFinal/MWTBaseline) was 1.8 (95%CI 1.19; 2.71, p=0.005). The MWT value in the pitolisant group was 80% higher than in the placebo group.


Figure 3: Changes in Epworth Sleepiness Scale Score (ESS) (mean ± SEM) from Baseline to week 7 in Harmony CTP study



The open-label, long-term Phase III study (HARMONY III) assessed the long term safety of pitolisant in patients suffering from narcolepsy (with or without cataplexy) over 12 months and with an extension of up to 5 years. 102 narcoleptic patients with or without cataplexy were included in the 12 months follow-up period. 68 patients completed the first 12 months period. 45, 38, 34 and 14 patients completed the 2, 3, 4 and 5 year follow-up periods, respectively.
The maximal dose received during the study was 36 mg / day in 85% of patients. After 12 months of treatment, improvements in EDS assessed by ESS score of remaining patients is of same magnitude as those observed in the other trials conducted in narcoleptic patients. The decrease in mean ESS score (SD) was -3.62 (4.63) after 1 year.
After 12 months of treatment with pitolisant, frequency of symptoms such as sleep attacks, sleep paralysis, cataplexy and hallucinations has been improved.
No major safety concern was identified. The safety results observed were similar to those reported in previous trials where pitolisant at 36 mg once daily was given for up to 3 months only.

Obstructive sleep apnoea (OSA)

Clinical efficacy
The efficacy of pitolisant in the treatment of Excessive Daytime Sleepiness (EDS) in patients with Obstructive Sleep Apnoea (OSA) has been studied in two pivotal clinical studies: HAROSA I and HAROSA II.

HAROSA I studied the efficacy and safety of pitolisant in the treatment of EDS in patients with Obstructive Sleep Apnoea syndrome (OSA), and treated by Continuous Positive Airway Pressure (CPAP), but still complaining of EDS. This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase. 244 patients were analyzed (183 pitolisant, 61 placebo), 83% male, average of 53 years old, 12% over 65 years. Patients had EDS (an Epworth Sleepiness Scale [ESS] score greater than or equal to 12) and were submitted to nCPAP therapy for a minimum period of 3 months and still complaining of EDS despite the efforts made beforehand to obtain an efficient nCPAP.

The primary efficacy variable was the change in Epworth Sleepiness Scale (ESS) Score between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 79.8% of the patient in the active treatment group and for 88.5% of the patients in the placebo group. The maximum dose is reached after a three-week titration, starting with 4.5 mg.


After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (table 1).

Table 1: overview of Efficacy results after 12 weeks in HAROSA I
Parameters       Treatment        Baseline      Final score Change                  Difference     P-value group (n)     score (at V2)     (at V6)                         from placebo 95% CI
Placebo (61)        14.6 (2.8)        12.1 (6.4)     -2.75
ESS (SD)                                                                            2.6[-3.9;-1.4]   P<0.001 Pitolisant (183)    14.9 (2.7)         9 (4.8)       -5.52



HAROSA II studied the efficacy and safety of pitolisant in the treatment of EDS in patients with Obstructive Sleep Apnoea syndrome (OSA) refusing the Continuous Positive Airway Pressure (CPAP) therapy. This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase followed by a 40-week open-label extension phase. 268 patients were analyzed (201 pitolisant, 67 placebo), 75% male, average of 52 years, 12% over 65 years. Patients had an Epworth Sleepiness Scale [ESS] score greater than or equal to 12 and were refusing to be treated by nCPAP therapy, and still complaining of EDS.

The primary efficacy variable was the change in Epworth Sleepiness Scale (ESS) score between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 82.5% of the patient in the active treatment group and for 86.6% of the patients in the placebo group.

After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (ANCOVA model adjusting for ESS and BMI at V2 and study center as random effect) (Table 2).


Table 2: overview of Efficacy results after 12 weeks in HAROSA II
Difference
Treatment         Baseline      Final score
Parameters                                                         Change         from placebo     P-value group (n)       score (at V2)     (at V6)
95% CI
Placebo (67)         15.7 (3.6)     12.2 (6.1)         -3.6
ESS (SD)                                                                        -2.8 [-4.0;-1.5]   P<0.001 Pitolisant (201)     15.7 (3.1)     9.1 (4.7)          -6.3



In an extended analysis the two HAROSA studies were compared and combined, showing significant improvements by pitolisant compared with placebo on the main parameters (ESS, OSleR test, Pichot Fatigue Scale and CGI).
Table 3: Main efficacy results in pooled analysis HAROSA I – HAROSA II Mean                95% CI                               p
OSleR Test (1)                  1.18                1.02, 1.35                        P=0.022 Pichot fatigue scale (2)        -1.27               -2.30, -0.23                      P=0.017 CGI  (3)                        -0.63               -0.84, -0.47                      P<0.001 1) mean ratio pitolisant/placebo
2) treatment effect
3) difference pitolisant-placebo

Open-label data

Patients who participated in the double-blind 12 weeks period of HAROSA I and HAROSA II studies, could participate in the 40 week open-label phase. The primary objective of the open-label phase was long-term safety and effectiveness of pitolisant up to 18 mg/day. Maintenance of effect of pitolisant in EDS in OSA patients has not been established in blinded, placebo-controlled studies. In HAROSA I, 1.5% of patients discontinued study participation during the open-label phase, due to lack of efficacy and 4.0% due to adverse events. In HAROSA II, 1.3% of patients discontinued study participation during the open-label phase due to lack of efficacy and 2.5% due to adverse events.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The exposure to pitolisant in healthy volunteers was assessed in studies involving more than 200 subjects that received doses of pitolisant in single administration up to 216 mg and for a duration up to 28 days.

Absorption
Pitolisant is well and rapidly absorbed with peak plasma concentration reached approximately three hours after administration. The steady-state (geometric mean, CV%) Cmax and AUC of the therapeutic dose (18 mg) is 35.5 ng/mL (59.2%) and 378 ng x h/mL (86.3%), respectively.
Upon repeated administrations, the steady state is achieved after 5-6 days of administration leading to an increased serum level around 2-fold. Inter individual variability is rather high (Geom CV% of 59.2 and 86.3 for Cmax and AUC0-24h respectively), some volunteers showing outlier high profile (without tolerance issues).
The pharmacokinetics of pitolisant is not influenced by concomitant food intake.

Distribution
Pitolisant exhibits high serum protein binding (91.4-95.2%) and demonstrates approximately equal distribution between red blood cells and plasma.
Pitolisant is widely distributed with an apparent volume of distribution of 5-10 L/kg.

Biotransformation
The metabolism of pitolisant in humans is well characterized and represents the major route of elimination.
The major non-conjugated metabolites are cleaved forms of pitolisant leading to inactive major carboxylic acid metabolites, three of which being major and in a lesser extent five hydroxylated/N-oxide derivatives in several positions found in urine and serum. By combining the contribution of enzyme determined in vitro with the exposure of the main metabolites identified in the mass balance study, the estimated overall contribution of CYP enzymes in pitolisant metabolism is of 60% for CYP2D6 and of ~ 30% for CYP3A4/3A5 when CYP2D6 phenotype is extensive metabolizer. Several conjugated metabolites were identified, the major ones (inactive) being two glycine conjugates of carboxylic acid metabolites of pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.

Inhibition/Induction
On liver microsomes, pitolisant and its major metabolites do not significantly inhibit the activities of the cytochromes CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2E1 or CYP3A4 and of uridine diphosphate glucuronosyl transferases isoforms UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 up to the concentration of 13.3 μM, a level considerably higher than the levels achieved with therapeutic dose.
Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 μM).
Based on in vitro data, pitolisant and its main metabolites may induce CYP3A4 and CYP2B6 at therapeutic concentrations and by extrapolation, CYP2C, UGTs and P-gp. A clinical study was conducted to assess the effect of pitolisant on CYP3A4 and CYP2B6 using midazolam and bupropion as a CYP3A4 and a CYP2B6 model substrate, respectively. Pitolisant does not affect the pharmacokinetic of bupropion and consequently is not a CYP2B6 or a CYP1A2 inducer and should be considered a borderline/weak inducer at clinically relevant concentrations.
In vitro studies indicate that pitolisant is neither a substrate nor an inhibitor of human P-glycoprotein and breast cancer resistance protein (BCRP). Pitolisant is not a substrate of OATP1B1, OATP1B3. Pitolisant is not a significant inhibitor of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2K at the tested concentration. Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 μM, the extrapolated IC50 of pitolisant is 0.795 μM (see section 4.5).

Elimination
Pitolisant has a plasma half-life of 10-12 hours. The elimination is mainly achieved via urine (approximately 90%) through pharmacologically inactive non conjugated and glycine and glucuronide conjugated metabolites. A small fraction (2.3%) was recovered in faeces.


Linearity/non-linearity
A cross-study assessment of single-dose data shows that pitolisant exposures increase proportionally with doses between 18 and 216 mg pitolisant but slightly more than dose-proportionally over the clinical dose range of 4.5 to 18 mg.

Special populations
There are unlikely to be any clinically relevant differences in the PK of pitolisant due to sex.
Pitolisant has not been studied in obese population with BMI >40 kg/m2.

Elderly
In 68 to 80 years old healthy volunteers the pharmacokinetics of pitolisant is not different compared to younger patients (18 to 45 years of age). Above 80 years old, kinetics show a slight variation without clinical relevance. Limited data are available in elderly. Therefore, dosing should be adjusted according to their hepatic status (see section 4.2 and 4.4).

Renal impairment
In patients with impaired renal function (stages 2 to 4 according to the international classification of chronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min), Cmax and AUC tended to be increased by a factor of 2.5 (see section 4.2). The underlying mechanism is unknown.

Hepatic impairment
In patients with mild hepatic impairment (Child-Pugh A), AUC increased by a factor 1.4 while Cmax remained unchanged, compared with normal healthy volunteers.
In patients with moderate hepatic impairment (Child-Pugh B), AUC increased by a factor 2.4, while Cmax remained unchanged (see section 4.2). Pitolisant pharmacokinetics after repeated administration in patients with hepatic impairment has not been evaluated yet.

Race
All studies have been performed mainly in Caucasians (Caucasians = 270; Black = 38; Asian = 20; Other = 3). Based on the data provided by the Applicant, the exposure appears to be similar between the different races.

CYP2D6 phenotypes and CYP3A polymorphism
The exposure to pitolisant was higher in the CYP2D6 poor metabolizers after a single dose and at steady state; Cmax and AUC(0-tau) was approximately 2.7-fold and 3.2-fold greater on Day 1 and 2.1-fold and 2.4- fold on Day 7. The serum pitolisant half-life was longer in CYP2D6 poor metabolizers compared to the extensive metabolizers.

In subjects that are CYP2D6 intermediate, extensive (normal) or ultra-rapid metabolizers, CYP2D6 is the main enzyme involved in the biotransformation of pitolisant, CYP3A is involved to a lesser extent.
CYP3A4 and CYP3A5 genetic polymorphisms are unlikely to have significant effect on the pharmacokinetic of pitolisant.
In these subjects, CYP2D6 inhibitors will have an effect on the pharmacokinetic of pitolisant, not CYP3A inhibitors. In subjects that are CYP2D6 ultra-rapid metabolizers, CYP3A inducers may lead to an even more rapid elimination of pitolisant and lower exposures compared to the other subgroups. This may result in exposures below therapeutic concentrations.

In subjects that are CYP2D6 poor metabolizers or are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking CYP3A inducers, CYP3A is significantly involved in the biotransformation of pitolisant and CYP2D6 is involved to a lesser extent. Only under these conditions, genetic polymorphisms in CYP3A4 and 3A5 may have a significant effect on the pharmacokinetic of pitolisant.
In subjects that are CYP2D6 poor metabolizers, CYP3A inhibitors and inducers will have an effect on the pharmacokinetic of pitolisant and CYP2D6 inhibitors to a much lesser extent. In subjects that are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking a CYP3A inducer, a CYP3A inhibitor will lead to a decrease in the contribution of CYP3A to the overall metabolism. However, the exposure is most likely similar to that in subjects that are not taking a CYP3A inducer. Thus, in this subpopulation, CYP3A inhibition is unlikely to affect the pharmacokinetic of pitolisant.