Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code: M09AX03

Mechanism of action

A nonsense mutation in DNA results in a premature stop codon within an mRNA. This premature stop codon in the mRNA causes disease by terminating translation before a full-length protein is generated.
Ataluren enables ribosomal readthrough of mRNA containing such a premature stop codon, resulting in production of a full-length protein.

Pharmacodynamic effects

Nonclinical in vitro experiments in nonsense mutation cellular assays and fish larvae cultured in an ataluren solution have shown that ataluren enabled ribosomal readthroughwith a bell-shaped (inverted-U shaped) concentration-response relationship. It is hypothetised that the in vivo dose response relationship may also be bell-shaped, but in vivo data were too limited to confirm this hypothesis in a mouse model for nmDMD and in humans.

Nonclinical in vitro studies suggest that continuous exposure to ataluren may be important for maximizing activity and that effects of the active substance on ribosomal read-through of premature stop codons reverse shortly after withdrawal of ataluren.
Clinical efficacy and safety

The efficacy and safety of Translarna were assessed in 2 randomised, double-blind, placebo-controlled, trials in nmDMD. The primary efficacy endpoint in both trials was change in 6 Minute Walk Distance (6MWD) at Week 48. Other endpoints included in both trials were time to persistent 10% worsening in 6MWD, change in time to run/walk 10 meters at Week 48, change in time to climb 4 stairs at Week 48, and change in time to descend 4 stairs at Week 48. Patients were required to have documented confirmation of the presence of a nonsense mutation in the dystrophin gene as determined by gene sequencing.

Study 1 evaluated 174 male patients, aged 5 to 20 years. All patients were required to be able to walk ≥75 meters without the need for assistive devices during a screening 6 -Minute Walk Test (6MWT).
The majority of patients in all treatment groups were Caucasian (90%). Patients were randomised in a 1:1:1 ratio and received ataluren or placebo 3 times per day (morning, midday, and evening), with 57 receiving ataluren 40 mg/kg/day (10, 10, 20mg/kg), 60 receiving ataluren 80 mg/kg/day (20, 20, 40 mg/kg), and 57 receiving placebo. In Study 1, a post hoc analysis of the primary endpoint showed that from baseline to Week 48, patients receiving ataluren 40 mg/kg/day had a 12.9 meters mean decline in 6MWD, and patients receiving placebo had a 44.1-meter mean decline in 6MWD (Figure 1). Thus, the mean change in observed 6MWD from baseline to Week 48 was 31.3 meters better in the ataluren 40 mg/kg/day arm than in the placebo arm (p=0.056). In a statistical based model the estimated mean difference was 31.7 meters (adjusted p=0.0367). There was no difference between ataluren 80 mg/kg/day and placebo.
These results indicate that ataluren 40-mg/kg/day slows the loss of walking ability in nmDMD patients.



Figure 1. Mean Change in 6-Minute Walk Distance (Study 1)
20

10


0
Meters (±SE)


-10
-12.9 m

-20

-30
TRANSLARNA 10 mg/kg, 10 mg/kg, 20 mg/kg (N=57)
-40                  Placebo (N=57)
-44.1 m

-50

-60
Baseline     6        12         18        24        30        36        42      48 Weeks

A post-hoc analysis of time to persistent 10% worsening in 6MWD showed that 26% of patients in the ataluren 40mg/kg/day arm had progressed at Week 48 compared to 44% in the placebo group (p=0.0652) (Figure 2). There was no difference between ataluren 80 mg/kg/day and placebo.
These results indicate that fewer patients receiving ataluren 40 mg/kg/day worsened in 6MWD over 48 weeks.

Figure 2. Kaplan-Meier Curve of Time to Persistent 10% 6MWD Worsening (Study 1) 100

90

80
Percent Not 10% Worsened


26% worsening
70

60                                                                                      44% worsening 
50

40
30
TRANSLARNA 10 mg/kg, 10 mg/kg, 20 mg/kg (N=57)

20              Placebo (N=57)

10

0         6          12         18        24        30        36        42    48       54           60 Weeks
In timed function tests (TFTs), tests of time to run/walk 10 meters, time to climb 4 stairs, and time to descend 4 stairs, ataluren-treated patients demonstrated smaller increases in the time it takes to 

run/walk 10 meters, climb 4 stairs, and descend 4 steps, indicating slowing of nmDMD progression relative to placebo.
The mean change in timed function tests from baseline to Week 48 was better in the ataluren 40mg/kg/day arm than placebo in time to run/walk 10 meters (better by 1.5 seconds), time to climb 4 stairs (better by 2.4 seconds), and time to descend 4 stairs (better by 1.6 seconds), Figure 3.

Figure 3. Mean Change in Timed Function Tests (Study 1)



6MWD Results in Patients with a Baseline 6MWD < 350 meters.
In patients with a baseline 6MWD < 350 meters, the mean change in observed 6MWD from baseline to Week 48 was 68 meters better in the ataluren 40mg/kg/day arm than in the placebo arm (p=0.0053).

In these patients, the mean change in timed function tests from baseline to Week 48 was better in the ataluren 40mg/kg/day arm than placebo in time to run/walk 10 meters (better by 3.5 seconds), time to climb 4 stairs (better by 6.4 seconds), and time to descend 4 stairs (better by 5.0 seconds).

Study 2 evaluated 230 male patients, ages 7 to 14 years. All patients were required to be able to walk ≥150 meters and less than 80% predicted without the need for assistive devices during a screening 6MWT. The majority of patients in both treatment groups were Caucasian (76%). Patients were randomised in a 1:1 ratio and received ataluren 40 mg/kg/day (n=115) or placebo (n=115) 3 times per day (morning, midday, and evening).

Ataluren-treated patients experienced clinical benefit as measured by numerically favorable differences versus placebo across the primary and secondary efficacy endpoints. As the primary endpoint (change in 6MWD from baseline to Week 48) did not reach statistical significance (p≤0.05), all other p-values should be considered nominal.

In the ITT population, the difference between the ataluren and placebo arms in mean change in observed 6MWD from baseline to Week 48 was 15.4 meters better in the ataluren 40 mg/kg/day arm than in the placebo arm. In a statistical based model the estimated mean difference was 13.0 meters (p=0.213), Figure 4. Separation between ataluren and placebo was maintained from Week 16 through the end of the study.



Figure 4. Mean Change in 6-Minute Walk Distance (Study 2)
0


-1 0


-2 0
M e te rs (± S E )



-3 0


-4 0
- 4 2 .2

-5 0

T R A N S L A R N A 1 0 m g /k g / 1 0 m g /k g , 2 0 m g /k g ( N = 1 1 4 )                  - 5 7 .6 -6 0
P la c e b o (N = 1 1 4 )


-7 0


-8 0
B a s e lin e                8                      16                       24                32   40   48 W eeks


Over 48 weeks, ataluren-treated patients showed less decline in muscle function, as evidenced by smaller increases in the time to run/walk 10 meters, climb 4 steps, and descend 4 steps in the ataluren-treated group relative to placebo. The differences favoring ataluren versus placebo in mean changes in timed function tests at Week 48 in the ITT population reached the threshold for a clinically meaningful difference (changes ~1 to 1.5 seconds).

The mean change in timed function tests from baseline to Week 48 was better in the ataluren 40 mg/kg/day arm than placebo in observed time to run/walk 10 meters (better by 1.2 seconds, p=0.117), time to climb 4 stairs (better by 1.8 seconds, p=0.058), and time to descend 4 stairs (better by 1.8 seconds, p=0.012),
Figure 5.



Figure 5. Mean Change in Timed Function Tests (Study 2)



Time to 10% worsening in 6MWD was defined as the last time that 6MWD was not 10% worse than baseline. In the ITT population, the hazard ratio for ataluren versus placebo was 0.75 (p=0.160), representing a 25% reduction in the risk of 10% 6MWD worsening.

Paediatric population

The safety, pharmacokinetics and exploratory effectiveness of Translarna were assessed in an open-label study in children between 2 and 5 years of age with nmDMD. The efficacy of Translarna in children aged 2 - 5 years has been established on extrapolation from patients aged >5years.

In the clinical program investigating the efficacy and safety of monotherapy ataluren in patients with nonsense mutation cystic fibrosis, no statistically significant effect was observed in the primary and key secondary clinical outcome measures (ppFEV1 and pulmonary exacerbation rate) in adults and children aged 6 years and older.

An open-label exploratory study (Study 045) was conducted in 20 subjects with nonsense mutation Duchenne muscular dystrophy (nmDMD) aged 2 to 7 years to explore quantitative levels of dystrophin in muscle tissue before and after 40 weeks of treatment with ataluren.
Dystrophin was measured using the electrochemiluminescence (ECL) and immunohistochemistry (IHC) assays. From each subject, 3 needle biopsies were taken from the gastrocnemius and the tibialis anterior at baseline and at the end of the treatment. Study 045 also included assessment of functional outcomes (i.e., the revised North Star Ambulatory Assessment [rNSAA] and Timed Function Tests [TFTs]).
The baseline median dystrophin levels as measured by ECL was 0.42% of normal (range 0.00% to 41.85%). At the end of the study, the median dystrophin level was 0.33% of normal (range 0.04% to 48.55%).
For IHC, the median percentage of positive fibres at baseline was 73% (range 0.42% to 99.6%).
At the end of the study, the median percentage of positive fibres was 66% (range 0.51% to 99.77%).
At the end of the study, the mean (median) worsening from baseline on the rNSAA was 0.1 (1.0) points in total score and the mean (median) change from baseline for the time to stand, to 

run or walk 10 meters, climb 4 stairs, and descend 4 stairs was -1.56 (-0.6), -0.41 (-0.35), -1.09 (-0.5), and -2.43 (-0.7) seconds, respectively.

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Administration of ataluren on a body weight-adjusted basis (mg/kg) resulted in similar steady-state exposures (AUC) among children and adolescents with nmDMD over a broad range of body weights.
Although ataluren is practically insoluble in water, ataluren is readily absorbed after oral administration as a suspension.

General characteristics of ataluren after administration

Absorption
Peak plasma levels of ataluren are attained approximately 1.5 hours after dosing in subjects who received medicinal product within 30 minutes of a meal. Based on the urinary recovery of radioactivity in a single- dose study of radiolabelled ataluren, the oral bioavailability of ataluren is estimated to be ≥55%. Ataluren plasma concentrations at steady state increase proportionally with increasing dose. Steady-state plasma concentrations are dose-proportional for ataluren doses between 10 and 50 mg/kg, and no accumulation is observed after repeated dosing.

Distribution
In vitro, ataluren is 99.6% bound to human plasma proteins and the binding is independent of plasma concentration. Ataluren does not distribute into red blood cells.

Biotransformation
Ataluren is metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, predominantly UGT1A9 in liver, intestine and kidney.

In vivo, the only metabolite detected in plasma after oral administration of radio-labelled ataluren was the ataluren-O-1β-acyl glucuronide; exposure to this metabolite in humans was approximately 8% of the plasma AUC of ataluren.

Elimination
Ataluren plasma half-life ranges from 2-6 hours and is unaffected either by dose or repeated administration.
The elimination of ataluren is likely dependent on hepatic and renal glucuronidation of ataluren followed by renal and hepatic excretion of the resulting glucuronide metabolite.
After a single oral dose of radiolabelled ataluren, approximately half of the administered radioactive dose is recovered in the faeces and the remainder was recovered in the urine.
In the urine, unchanged ataluren and the acyl glucuronide metabolite account for <1% and 49%, respectively, of the administered dose.

Linearity/non-linearity
Steady-state plasma concentrations are dose-proportional for ataluren doses between 10 and 50 mg/kg, and no accumulation is observed after repeated dosing. Based on data in healthy volunteers, the relative bioavailability of ataluren is approximately 40% lower at steady-state than after the initial dose. The onset of reduction in relative bioavailability is estimated to occur approximately 60 hours after the first dose. The steady-state is established after approximately two weeks of thrice daily dosing.

Characteristic in specific groups of subjects or patients

Age
Based on data from subjects ranging in age from 2 years to 57 years, there is no apparent effect of age on ataluren plasma exposure. Age-adjusted dosing is not required.

The pharmacokinetics of ataluren has been evaluated in study PTC124-GD-030 over a duration of 4 weeks. Ataluren plasma concentrations in patients from 2 to less than 5 years old were consistent with those seen in patients above the age of 5 years receiving the 10/10/20 mg/kg dose regimen.

Gender
Females were not studied in nmDMD clinical trials. However there were no apparent effects of gender on ataluren plasma exposure in other populations.
Race
It is unlikely that the pharmacokinetics of ataluren are significantly affected by UGT1A9 polymorphisms in a Caucasian population. Due to the low number of other races included in the clinical studies, no conclusions can be drawn on the effect of UGT1A9 in other ethnic groups.

Renal impairment
No dosage adjustment is required for patients with mild or moderate renal impairment.In a pharmacokinetic study in subjects with varying degrees of renal impairment, following a single dose administration, ataluren plasma exposure changed by -13%, 27%, and 61% for the mild, moderate and severe groups, respectively, and 46% for the end-stage renal disease group compared with the normal renal function group. In addition, a 3 to 8 fold increase in ataluren metabolite has been reported in patients with severe renal impairment (eGFR <30 ml/min).
Following multiple dosing, the increase in ataluren and ataluren metabolite is anticipated to be higher in patients with severe renal impairment and end-stage renal disease when compared with patients with normal renal function at steady state. Patients with severe renal impairment (eGFR <30 ml/min) or end-stage renal disease should be treated with ataluren only if the anticipated clinical benefit outweighs the potential risk (see sections 4.2 and 4.4).
Hepatic impairment
Based on a pharmacokinetic assessment conducted in groups with either mild, moderate or severe hepatic impairment versus a control group of healthy subjects, no dose adjustment is required for patients with any degree of hepatic impairment. No apparent differences of the total ataluren exposure in the control, mild, and severe hepatic impairment groups were observed. An approximately 40% decrease of mean total ataluren exposure in the moderate hepatic impairment group versus the control group was noted probably due to the small sample size and variability.

Non-ambulatory
There were no apparent differences in either steady-state relative bioavailability or apparent clearance due to loss of ambulation. No dosing adjustment is needed for patients who are becoming nonambulatory.