Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

6.1   Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics; ATC code: N03AX26 
Mechanism of action

Fenfluramine is a serotonin releasing agent, and thereby stimulates multiple 5-HT receptor sub-types through the release of serotonin. Fenfluramine may reduce seizures by acting as an agonist at specific serotonin receptors in the brain, including the 5-HT1D, 5-HT2A, and 5-HT2C receptors, and also by acting on the sigma-1 receptor. The precise mode of action of fenfluramine in Dravet syndrome and Lennox-Gastaut syndrome is not known.

Clinical efficacy
Dravet syndrome
Children and young adults with Dravet syndrome
The effectiveness of fenfluramine in children and young adults with Dravet syndrome was evaluated in two randomised, multicentre, placebo-controlled studies.

Study 1 (N=119) was a 3-arm, multicentre, randomised, double-blind, parallel group, placebo-controlled study consisting of a 6-week baseline period followed by a 2-week titration period and a 12-week maintenance period for a total of 14 weeks treatment. Eligible patients were randomised 1:1:1 to one of two doses of fenfluramine (0.7 mg/kg/day or 0.2 mg/kg/day, maximum 26 mg/day) or placebo. The mean (standard deviation) age of patients enrolled in Study 1 was 9.0
(4.7) years, with a range of 2 to 18 years. The majority of patients were ≥6 years of age (73.9%) and the minority <6 years (26.1%), male (53.8%), and white (82.4%). All enrolled patients were inadequately controlled on at least one anti-epileptic medicine, with or without vagal nerve stimulation and/or ketogenic diet. Patients were taking between one and five anti-epileptic medicines at study entry. The most frequently used concomitant anti-epileptic medicines (≥25% overall) were valproate (59.6%), clobazam (58.8%), and topiramate (25.2%). In Study 1, the median baseline convulsive seizure frequency per 28 days was 34.0, 17.5, and 21.2 in the placebo, fenfluramine 0.2 mg/kg/day, and fenfluramine 0.7 mg/kg/day groups, respectively.



Table 5: Dravet syndrome: Study 1 and Study 3 results of primary and selectedsecondary efficacy endpoints
Study 1                                 Study 3

Placebo   Fenfluramine     Fenfluramine    Placebo        Fenfluramine     Fenfluramine 0.2 mg/kg/day    0.7 mg/kg/day                  0.2 mg/kg/day    0.7 mg/kg/day 

Convulsive     N                 39           39              40              48               46              48 12.7            18.0            13.0
(4.0, 229.3)    (4.0, 1464.0)   (2.7, 2700.7)
Seizure        Baseline.        34.0          17.5            21.2                                              ) Frequency      Median (min,     (3.3,     (4.8, 623.5)    (4.9, 127.0) max)            147.3)
Maintenance    N                 39           39              40             48                46             48 7.6
(0.0, 2006.8) period         At end of        25.7          17.1             4.9          10.6                             3.2 maintenance      (3.6,     (0.0, 194.3)     (0, 105.5)    (1.0, 139.0)                    (0.0, 3651.7) period.         204.7)
Median (min,
max)
Reduction in      -          36.7%           67.3%             -                             65.7% mean monthly                p=0.016         p<0.001                         49.3%          p< 0.0001 p< 0.0001 baseline- adjusted
Convulsive
Seizure
Frequency compared to



Study 1                                      Study 3

Placebo      Fenfluramine       Fenfluramine       Placebo     Fenfluramine    Fenfluramine 0.2 mg/kg/day      0.7 mg/kg/day                  0.2 mg/kg/day
0.7 mg/kg/day


% reduction       Number (%) of          4         17 (43.6%)         29 (72.5%)         4 (8.3%)     21 (45.7%)     33 (68.8%) in convulsive     patients with                    ES=33.3            ES=62.2                         ES=37.3%       ES=60.4% (10.3%) seizures          ≥50%                                                                                 RR: 5.48       RR: 8.25 %      RR:         %      RR: reduction in                     4.25               7.07
Maintenance       monthly period            convulsive seizures - change from baseline

Effect size1
Relative Risk
Number (%) of      2 (5.1%)      10 (25.6%)         21 (52.5%)         2 (4.2%)     9 (19.6%)     23 (47.9%) patients with                    ES=20.5%           ES=47.4%                        ES=15.4%       ES=43.7% RR: 4.70       RR: 11.50
≥75%                               RR: 5.00          RR: 10.24 reduction in monthly convulsive seizures
- change from baseline
Effect size1
Relative Risk
Number (%) of       0 (0%)        6 (15.4%)          6 (15.0%)          0 (0%)      1 (2.2%)       10 patients with                     ES=15.4%           ES=15.0%                                      (20.8%) ≥100% reduction in monthly convulsive seizures - change from baseline

Effect size1
Longest seizure-free interval        9.5 days        15.0 days         25.0 days        10.0 days     18.5 days        30 days p=0.0002        p<0.0001
(median)                                              p=0.035           p<0.001 
Titration + maintenance period
1   Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; RR: Relative Risk 
Study 2 (previously known as 1504) (N=87) was a 2-arm, multicentre, randomised, double-blind, parallel group, placebo-controlled study consisting of a 6-week baseline period followed by a 3-week titration period and a 12-week maintenance period for a total of 15 weeks treatment. Eligible patients were randomised 1:1 to fenfluramine 0.4 mg/kg/day (maximum 17 mg/day) or placebo added to their stable standard of care regimen of stiripentol (plus clobazam and/or valproate) and possibly other anti-epileptic medicines. The mean (standard deviation) age of patients enrolled in Study 2 was 9.1 (4.80) years, with a range of 2 to 19 years. The majority of patients were ≥6 years of age (72.4%)and the minority <6 years (27.6%), male (57.5%) and, where reported, white (59.8%). All enrolled subjects were inadequately controlled on at least one anti-epileptic medicine, which included stiripentol, with or without vagal nerve stimulation and/or ketogenic diet. The median baseline convulsive seizure frequency per 28 days was 10.7 and 14.3 in the placebo and fenfluramine 0.4 mg/kg/day groups, respectively.

Table 6. Dravet syndrome: Study 2 (previously known as Study ZX008-1504) results of primary and selected secondary efficacy endpoints
Study 2
Placebo + stiripentol    Fenfluramine 0.4 mg/kg/day + stiripentol
Convulsive Seizure            N                                           44                            43 Frequency                     Baseline. Median (min,                     10.7                          14.3 max)                                   (2.7, 162.7)                 (2.7, 213.3) Maintenance period            N                                           44                            42 At end of maintenance                      11.4                          3.9 period.                                (0.7, 169.3)                 (0.0, 518.0) Median (min, max)
Reduction in mean monthly                    -                        54.9 % baseline-adjusted                                                     p<0.001 Convulsive Seizure
Frequency compared to
Placebo
% reduction in convulsive Number (%) of patients                       4 (9.1%)                    23 (54.8%) seizures                      with ≥50% reduction in                                                ES=45.7 monthly convulsive                                                    RR: 6.02 Maintenance period            seizures - change from baseline
Effect size1
Relative Risk
Number (%) of patients                   2 (4.5%)                    17 (40.5%) with ≥75% reduction in                                               ES=36.0% monthly convulsive                                                    RR: 8.90 seizures - change from baseline
Effect size1
Relative Risk
Number (%) of patients                   0 (0%)                       2 (4.8%) with ≥100% reduction in                                               ES=4.8% monthly convulsive seizures - change from baseline
Effect size1
Longest seizure-free interval (median)                                13.0 days                     22.0 days p=0.004
Titration + maintenance period
1   Effect size (ES) (Risk difference) calculated as proportion of Active-Placebo; RR: Relative Risk 

Adults
The Dravet syndrome population in Study 1 and Study 2 was predominantly paediatric patients, with only 7 adult patients who were 18-19 years old (3.4%), and therefore limited efficacy and safety data were obtained in the adult Dravet syndrome population.

Open-label data

Dravet syndrome patients who participated in Study 1 and Study 2 could participate in an open-label extension study (Study 3). The primary objective of the open-label study was long-term effectiveness and safety of fenfluramine at doses of 0.2 to 0.7 mg/kg/day, whereby the dose of fenfluramine could be titrated to optimize treatment. Data are reported for 330 patients who participated in the open-label study and received fenfluramine for up to 3 years (median treatment period: 631 days; range: 7-1086).
A total of 23% of subjects discontinued study participation during the open-label extension treatment period, including 15% due to lack of efficacy and 1% due to adverse events.

Lennox-Gastaut syndrome
Children and adults with Lennox-Gastaut syndrome
The effectiveness of Fintepla for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 to 35 years of age was evaluated in a randomized, double-blind, placebo-controlled study (Study 4 Part 1).

Study 4 Part 1 compared a 0.7 mg/kg/day (N=87) and a 0.2 mg/kg/day (N=89) dose (up to a maximum dose per day of 26 mg/kg) of fenfluramine with placebo. Patients had a diagnosis of Lennox-Gastaut syndrome and were inadequately controlled on at least one anti-epileptic medicine, with or without vagal nerve stimulation and/or ketogenic diet. The study had a 4-week baseline period, during which patients were required to have a minimum of 8 drop seizures while on stable anti-epileptic medicine therapy. Drop seizures included: generalized tonic-clonic, secondarily generalized tonic-clonic, tonic, atonic, or tonic-atonic seizures that were confirmed to result in drops. The baseline period was followed by randomization into a 2-week titration period and a subsequent 12-week maintenance period, where the dose of fenfluramine remained stable.

In Study 4 Part 1, 99% of patients were taking between 1 and 4 concomitant anti-epileptic medicines. The most frequently used concomitant anti-epileptic medicines (in at least 25% of patients) were clobazam (45.2%), lamotrigine (33.5%), and valproate (55.9%).

The primary efficacy endpoint in Study 4 Part 1 was percent change from baseline in the frequency of drop seizures per 28 days during the combined 14-week titration and maintenance periods (i.e., treatment period) in the 0.7 mg/kg/day group compared to the placebo group. Key secondary endpoints included the proportion of patients who achieve a ≥50% reduction from baseline in drop seizure frequency per 28 days for the fenfluramine 0.7 mg/kg/day group compared to the placebo group and proportion of patients who achieve improvement (minimally, much, or very much improved) in the Clinical Global Impression − Improvement (CGI-I) as assessed by the Principal Investigator for the fenfluramine 0.7 mg/kg/day group compared to the placebo group.

In Study 4 Part 1, the median percent change from baseline (reduction) in the frequency of drop seizures per 28 days was significantly greater for the 0.7 mg/kg/day dose group of fenfluramine compared with the placebo group (Table 6). A reduction in drop seizures was observed within 2 weeks of initiating treatment with fenfluramine, and the effect remained consistent over the 14-week treatment period.

Among subjects with ≥124 drop seizures per 28 days during Baseline, the reduction in DSF were -19.98%, - 7.37%, -11.21% for subjects in the fenfluramine 0.7 mg/kg/day group, 0.2 mg/kg/day group, and placebo group respectively.
Table 7              Lennox-Gastaut syndrome: results of selected endpoints in Study 4 Part 1 (Maintenance Period)
Fenfluramine
Placebo                       0.7 mg/kg/day
(N = 87)                         (N = 87)
Primary Endpoint: Percentage Change from BL in DSF During M
DSF Summary Statistics a
Median at BL                                                            53.00                        82.00 Median during M                                                         47.33                        55.73 Median Percentage Change from BL During M                               -7.28                       -27.16 Nonparametric Model b p-value for comparison with placebo                                      —                          0.0018 HL Estimate for Median Difference (A-P)
Estimate (Std Err)                                                       —                        -20 (5.795) 95% CI                                                                   —                       -31.61, -8.89 Key Secondary Endpoint: Percentage of Patients with ≥ 50% Reduction from BL in DSF (50% Responder Rate) During M
≥ 50% reduction in DSF, n (%)                                         11 (12.6)                    27 (31.4) p-value for comparison with placebo c                                                               0.0044 Key Secondary Endpoint: Percentage of Patients with Improvement d on the CGI-I Investigator Rating at End of M Subjects with score 1, 2, or 3, n (%)                                27 (33.8)                    39 (48.8) p-value vs placebo e                                                                               0.0567 ANCOVA = analysis of covariance; A-P = active group–placebo group; BL = Baseline Period; CGI I = Clinical Global Impression – Improvement; CI = confidence interval; DSF = drop seizure frequency per 28 days; HL = Hodges-Lehmann; Std Err = standard error; T+M = Titration and Maintenance Periods a BL, T+M, and percentage change from BL in M values for seizure frequency per 28 days are presented in original scale.
b Results are based on a nonparametric ANCOVA model with treatment group (3 levels) and weight strata (< 37.5 kg, ≥ 37.5 kg) as factors, rank of BL seizure frequency as a covariate, and rank of percentage change from BL in seizure frequency during treatment (M) as response c   Based on a logistic regression model that included a categorical response variable (achieved percentage point reduction, yes or no), weight group strata (< 37.5 kg, ≥ 37.5 kg), and Baseline DSF as a covariate.
d   Minimally, much, or very much improved e   Based on a Cochran-Mantel-Haenszel test comparing active treatment with placebo, after adjusting for weight strata 

The median percent reduction from baseline in drop seizure frequency per 28 days for the lower dose of fenfluramine (0.2 mg/kg/day) during the Maintenance Period did not reach statistical significance compared to placebo (Median change between 0.2 group of patients and placebo in % change from baseline during Maintenance Period -11.48 [95% CI -26.61, 3.31]).

The seizure type with the greatest median percentage change from Baseline in the fenfluramine 0.7 mg/kg/day group relative to the placebo group was generalised tonic-clonic seizures (-45.7% fenfluramine 0.7 mg/kg/day [n=38] versus 3.7% placebo [n=38]).


Lennox-Gastaut patients who completed Study 4 Part 1 could participate in Part 2, an open-label, 52- week flexible-dose extension study for patients with Lennox-Gastaut syndrome who completed Part 1. The primary objective of Study 4 Part 2 was to assess the long-term safety and tolerability of fenfluramine at doses of 0.2 mg/kg/day to 0.7 mg/kg/day. All patients received fenfluramine 0.2 mg/kg/day for 1 month, then the dose was titrated to optimize treatment.

Among the 172 LGS subjects treated with Fintepla for ≥ 12 months, 46.5% had received a mean daily dose of 0.4 to <0.6 mg/kg/day, 33.7% received a mean daily dose ≥ 0.6 mg/kg/day, 19.8% received a mean daily dose of >0 to <0.4 mg/kg/day.

Data are reported for 247 patients who enrolled in Study 4 Part 2 and received fenfluramine for a median duration of 364 days (range: 19-542 days). A total of 143 subjects had completed the study, 19 subjects were ongoing, and 85 subjects had withdrawn. The most common reason for discontinuation was lack of efficacy (55 [22.3%]), adverse event (13 [5.3%]), and withdrawal by subject (13 [5.3%]).


Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Fintepla in one or more subsets of the paediatric population in Dravet syndrome (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Pharmacokinetics
The pharmacokinetics of fenfluramine and norfenfluramine were studied in healthy subjects and in paediatric patients with Dravet syndrome.

Absorption
Fenfluramine has a time to maximum plasma concentration (Tmax) in the range of 3 to 5 hours at steady state. The absolute bioavailability of fenfluramine is approximately 68-83%. There was no effect of food on the pharmacokinetics of fenfluramine or norfenfluramine.
For fenfluramine, the Cmax occurs ~3 h following a single oral dose in healthy volunteers and is 28.6 ng/mL following a dose of 0.35 mg/kg and 59.3 ng/mL following a dose of 0.7 mg/kg fenfluramine.
The AUCinf is 673 ng × h/mL and 1660 ng × h/mL following 0.35 mg/kg and 0.7 mg/kg, respectively.
For norfenfluramine, the Cmax occurs ~12 h following a single oral dose in healthy volunteers and is 11.7 ng/mL and 16.1 ng/mL following a dose of 0.354 mg/kg or 0.78 mg/kg, respectively. The AUCinf is 798 ng × h/mL and ~800 ng × h/mL following 0.35 mg/kg and 0.7 mg/kg, respectively. Cmax and AUCinf of fenfluramine appear dose proportional over the 0.35 to 0.7 mg/kg dose range in healthy volunteers. The Cmax and AUCinf of norfenfluramine are less than dose proportional over the 0.35 to 0.7 mg/kg dose range in healthy volunteers. The AUCinf increase was 0.5-fold for the 0.7 mg/kg dose compared to the 0.35 mg/kg dose. The Cmax increase was 0.7-fold for the 0.7 mg/kg dose compared to the 0.35 mg/kg dose.

In paediatric Dravet syndrome patients following fenfluramine dosing of 0.2 mg/kg/day, administered twice daily, steady state exposure (AUC0-24) is 371 ng*h/mL for fenfluramine and 222 ng*h/mL for norfenfluramine. In paediatric patients following fenfluramine dosing of 0.7 mg/kg/day, administered twice daily with a maximum of 26 mg/day; steady state AUC0-24 is 1400 ng*h/mL for fenfluramine and 869 ng*h/mL for norfenfluramine following a dose of 0.7 mg/kg/day, administered twice daily. Cmax,ss was 68.6 ng/mL for fenfluramine and 37.8 ng/mL for norfenfluramine. When stiripentol is given concomitantly, the steady state AUC0-24 is 1030 ng*h/mL for fenfluramine and 139 ng*h/mL for norfenfluramine following a dose of 0.2 mg/kg/day, administered twice daily; the steady state AUC0-24 is 3240 ng*h/mL for fenfluramine and 364 ng*h/mL for norfenfluramine following a dose of 0.35 mg/kg/day, administered twice daily.

In paediatric and adult patients with Lennox-Gastaut syndrome who receive Fintepla 0.7 mg/kg/day, administered twice daily, up to a total daily dose of 26 mg fenfluramine, steady-state systemic exposure (Cmax and AUC0-24h) of fenfluramine is slightly lower on average but not considered to be meaningfully different than in patients with Dravet syndrome.


The plasma half-life of fenfluramine and norfenfluramine indicates that approximately 94% of steady-state would be reached in approximately 4 days for fenfluramine and 5 days for norfenfluramine (4 half-lives). In healthy subjects, the Cmax accumulation ratio is 3.7-fold for fenfluramine and 6.4-fold for norfenfluramine and the AUC0-24 accumulation ratio is 2.6-fold for fenfluramine and 3.7-fold for norfenfluramine.

Distribution

Fenfluramine is 50% bound to human plasma proteins in vitro and binding is independent of fenfluramine concentrations. The geometric mean (CV%) volume of distribution (Vz/F) of fenfluramine is 11.9 (16.5%) L/kg following oral administration of fenfluramine in healthy subjects.

Biotransformation
Over 75% of fenfluramine is metabolised to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. Norfenfluramine is then deaminated and oxidized to form inactive metabolites. The extent to which these inactive metabolites are present in plasma and urine is unknown. The involvement of enzymes other than CYPs (e.g. UGTs) in the metabolism of norfenfluramine is unknown, but literature data indicate that norfenfluramine may be glucuronidated to a significant extent.

Transporters

Fenfluramine and norfenfluramine were not in vitro substrates of P-glycoprotein, BCRP, OATP1B1, OATP1B3, OATP1A2, OATP2B1, OCT1, OAT1, OAT3, OCT2, MATE1 and MATE2-K.

Elimination

Most of an orally administered dose of fenfluramine (>90%) is excreted in the urine mainly as metabolite; less than 5% is found in faeces. The geometric mean (CV%) clearance (CL/F) of fenfluramine is 6.9 L/h (29%) and the half-life is 20 hours following oral administration of fenfluramine in healthy subjects. The elimination half-life of norfenfluramine is ~30 h.

Special populations

Genetic polymorphisms
No impact of genotype in CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4 on fenfluramine or norfenfluramine PK was observed.

Renal impairment
Renal elimination is the predominant route of elimination of fenfluramine-related products, with more than 90% of the administered dose eliminated in the urine as parent or metabolites. There are no human clinical data on the effect of renal impairment on the PK of fenfluramine and norfenfluramine.

Hepatic impairment
No studies on the effect of hepatic impairment on the PK of fenfluramine in adults or children were found. With hepatic metabolism of fenfluramine, plasma drug concentrations may be affected in patients with significant hepatic impairment. Subjects with moderate or severe hepatic impairment were excluded from the phase 3 clinical trials.

Body weight
Drug clearance and PK exposure of fenfluramine and norfenfluramine are consistent across a broad range of BMI (12.3 to 35 kg/m2).

Gender
The pharmacokinetics of fenfluramine and norfenfluramine were consistent between males and females.

Race
The evaluation was limited by the small sample size of non-white subjects that no conclusion on the effect of race on the pharmacokinetics can be made. The genetic polymorphs of the enzymes that metabolize fenfluramine are similar across races, only their frequency differs. Thus, although the mean exposure may differ slightly depending on race, the range of exposure would be expected to be similar.