Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: other muscle relaxants, peripherally acting agents, ATC code: M03AX01

Botulinum neurotoxin type A blocks cholinergic transmission at the neuromuscular junction by inhibiting the release of acetylcholine. The nerve terminals of the neuromuscular junction no longer respond to nerve impulses, and secretion of the neurotransmitter at the motor endplates is prevented (chemical denervation). Recovery of impulse transmission is re-established by the formation of new nerve terminals and reconnection with the motor endplates.

Mechanism of action
The mechanism of action by which botulinum neurotoxin type A exerts its effects on cholinergic nerve terminals can be described by a four-step sequential process which includes the following steps: 
•     Binding: The heavy chain of botulinum neurotoxin type A binds with exceptionally high selectivity and affinity to receptors only found on cholinergic terminals.
•     Internalisation: Constriction of the nerve terminal’s membrane and absorption of the toxin into the nerve terminal (endocytosis).
•     Translocation: The amino-terminal segment of the neurotoxin’s heavy chain forms a pore in the vesicle membrane, the disulphide bond is cleaved and the neurotoxin’s light chain passes through the pore into the cytosol.
•     Effect: After the light chain is released, it very specifically cleaves the target protein (SNAP 25) that is essential for the release of acetylcholine.



Complete recovery of endplate function/impulse transmission after intramuscular injection normally occurs within 3-4 months as nerve terminals sprout and reconnect with the motor endplate.

Results of the clinical studies
Therapeutic equivalence of XEOMIN as compared to the comparator product Botox containing the botulinum toxin type A complex (onabotulinumtoxinA, 900 kD) was shown in two comparative single-dosing Phase III studies, one in patients with blepharospasm (study MRZ 60201-0003, n=300) and one in patients with cervical dystonia (study MRZ 60201-0013, n=463). Study results also suggest that XEOMIN and this comparator product have a similar efficacy and safety profile in patients with blepharospasm or cervical dystonia when used with a dosing conversion ratio of 1:1 (see section 4.2).

Blepharospasm
XEOMIN has been investigated in a Phase III, randomised, double-blind, placebo-controlled, multi- center trial in a total of 109 patients with blepharospasm. Patients had a clinical diagnosis of benign essential blepharospasm, with baseline Jankovic Rating Scale (JRS) severity subscore ≥ 2, and a stable satisfactory therapeutic response to previous administrations of the comparator product (onabotulinumtoxinA ).
Patients were randomised (2:1) to receive a single administration of XEOMIN (n=75) or placebo (n=34) at a dose that was similar (+/- 10 %) to the 2 most recent Botox injection sessions prior to study entry. The highest dose permitted in this study was 50 units per eye; the mean XEOMIN dose was 32 units per eye.
The primary efficacy endpoint was the change in the JRS severity subscore from baseline to Week 6 post-injection, in the intent-to-treat (ITT) population, with missing values replaced by the patient’s most recent value (last observation carried forward). In the ITT population, the difference between the XEOMIN group and the placebo group in the change of the JRS severity subscore from baseline to Week 6 was -1.0 (95% CI -1.4; -0.5) points and statistically significant (p <0.001).
Patients could continue with the Extension Period if a new injection was required. The patients received up to five injections of XEOMIN with a minimum interval between two injections of at least six weeks (48-69 weeks total study duration and a maximum dose of 50 units per eye.
Over the entire study, the median injection interval in subjects treated with XEOMIN ranged between 10.14 (1st interval) and 12.00 weeks (2nd to 5th interval).

Another double-blind, placebo-controlled Phase III clinical trial with an open-label extension period investigated efficacy of XEOMIN in a total of 61 patients, with a clinical diagnosis of benign essential blepharospasm and baseline Jankovic Rating Scale (JRS) severity subscore ≥ 2, who were botulinum toxin treatment-naïve, i.e., who had not received any botulinum toxin treatment of blepharospasm for at least 12 months prior to administration of XEOMIN. In the main period (6-20 weeks), the patients were randomised to receive a single administration of XEOMIN at the doses of 12.5 units per eye (n=22), 25 units per eye (n=19) or placebo (n=20), respectively. The patients requiring a new injection could continue with the extension period and received one further injection of XEOMIN.
In the main period, the median duration of the treatment interval was 6 weeks in the placebo group, 11 weeks in the group treated with 12.5 units per eye, and 20 weeks in the group treated with 25 units per eye. The ANCOVA LS mean difference vs. placebo (95% CI) in the change of the JRS severity subscore from baseline to week 6 was -1.2 (-1.9, -0.6) in the group administered 25 units XEOMIN per eye and found statistically significant, whereas the respective difference vs. placebo in the group given XEOMIN 12.5 units was -0.5 (-1.1, 0.2) which was not statistically significant.
During the extension period the patients received an injection of XEOMIN (n=39) at a mean dose close to 25 units (range: 15-30 units) per eye, and the median duration of the treatment interval was 19.9 weeks.

Spasmodic torticollis
XEOMIN has been investigated in a Phase III, randomised, double-blind, placebo-controlled, multi- center trial in a total of 233 patients with cervical dystonia. Patients had a clinical diagnosis of predominantly rotational cervical dystonia, with baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20.
Patients were randomised (1:1:1) to receive a single administration of XEOMIN 240 units (n=81), XEOMIN 120 units (n=78), or placebo (n=74). The number and sites of the injections were to be determined by the Investigator.
The primary efficacy variable was the LS mean change from Baseline to Week 4 following injection in the TWSTRS-Total score, in the Intent-to-Treat (ITT) Population with missing values replaced by the patient’s baseline value (full statistical model). The change in TWSTRS-Total score from Baseline to Week 4 was significantly greater in the XEOMIN groups, compared with the change in the placebo group (p <0.001 across all statistical models). These differences were also clinically meaningful: e.g. -9.0 points for 240 units vs. placebo, and -7.5 points for 120 units vs. placebo in the full statistical model.
Patients could continue with the Extension Period if a new injection was required. The patients received up to five injections of 120 units or 240 units of XEOMIN with a minimum interval between two injections of at least six weeks (48-69 weeks total study duration). Over the entire study, the median injection interval in subjects treated with XEOMIN ranged between 10.00 (1st interval) and 13.14 weeks (3rd and 6th interval). Based on the patient’s request for retreatment, the median duration of response following XEOMIN treatment in this study (both double-blind and the open-label extension period) was 12 weeks (Interquartile ranges: 9 to 15 weeks). In the majority of injection cycles (96.3%) the time to retreatment was between 6 and 22 weeks and in individual cases up to 28 weeks.

Post-stroke Spasticity of the upper limb
In the pivotal study (double-blind, placebo-controlled, multicentre) conducted in patients with post- stroke spasticity of the upper limb, 148 patients were randomised to receive XEOMIN (n=73) or Placebo (n=75). The cumulative dose after up to 6 repeated treatments in a clinical trial was in average 1333 units (maximum 2395 units) over a period of up to 89 weeks.

As determined for the primary efficacy parameter (response rates for the wrist flexors Ashworth Scale score at Week 4, response defined as improvement of at least 1-point in the 5-point Ashworth Scale score), patients treated with XEOMIN (response rate: 68.5%) had a 3.97 fold higher chance of being responders relative to patients treated with placebo (response rate: 37.3%; 95% CI: 1.90 to 8.30; p <0.001, ITT population).

This fixed dose study was not designed to differentiate between female and male patients, nevertheless in a post-hoc analysis the response rates were higher in female (89.3 %) compared to male (55.6%) patients, the difference being statistically significant for women only. However, in male patients response rates in Ashworth Scale after 4 weeks in XEOMIN treated patients were consistently higher in all muscle groups treated compared to placebo. Based on the patient’s request for retreatment, the median duration of effect in this pivotal study followed by the open-label extension period was 14 weeks (Interquartile ranges: 13 to 17 weeks) and in the majority of injection cycles (95.9%) the time to retreatment was between 12 and 28 weeks.

Responder rates were similar in men compared to women in the open label extension period of the pivotal study (flexible dosing was possible in this trial period) in which 145 patients were enrolled and up to 5 injection cycles were performed, as well as in the observer-blind study (EudraCT Number 2006- 003036-30) in which efficacy and safety of XEOMIN in two different dilutions in 192 patients were assessed in patients with upper limb spasticity of diverse aetiology.

Another double-blind, placebo-controlled Phase III clinical trial enrolled a total of 317 treatment-naïve patients with spasticity of the upper limb who were at least three months post-stroke. During the Main Period (MP) a fixed total dose of XEOMIN (400 units) was administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups (n=210). The confirmatory analysis of the primary and co-primary efficacy variables at week 4 post-injection demonstrated statistically significant improvements in the responder rate of the Ashworth score, or changes from baseline in the Ashworth score and the Investigator's Global Impression of Change.
296 treated patients completed the MP and participated in the first Open-label Extension (OLEX) cycle. During the Extension Period patients received up to three injections. Each OLEX cycle consisted of a single treatment session (400 units of XEOMIN total dose, distributed flexibly among all affected muscles) followed by a 12 week observation period. The overall study duration was 48 weeks.

Moderate to severe Vertical Lines between the Eyebrows seen at frown (Glabellar Frown Lines) A total of 994 subjects with moderate to severe glabellar frown lines at maximum frown participated in studies with XEOMIN in the indication glabellar frown lines. Of these, 169 subjects (≥ 18 years) were treated with XEOMIN in the Main Period of the pivotal Phase III double-blind placebo controlled trial and 236 subjects were treated in the Open-label Extension (OLEX) of that study.
Treatment success was defined as a ‘none’ or ‘mild’ assessment on a 4-point Facial Wrinkle Scale assessed by the investigator at week 4 at maximum frown. The study demonstrated a statistically significant and clinically relevant efficacy of 20 units XEOMIN when compared to placebo. The overall success rate was 51.5% in the XEOMIN group vs. 0% in the placebo group. No worsening was observed in any patient treated with XEOMIN in the pivotal study. This was validated by the higher number of responders at Day 30 according to the Facial Wrinkle Scale at maximum frown by both the investigator and the patient’s assessment showing a significantly higher proportion of responders among the patients receiving 20 units XEOMIN compared to placebo.

Subgroup analysis showed that efficacy in patients older than 50 years is lower compared to younger patients. Of those, 113 subjects were in the age of 50 years or younger and 56 subjects were older than 50 years of age. Efficacy in men is lower compared to women. Of those, 33 subjects were male and 136 subjects were female.

Therapeutic equivalence of XEOMIN as compared to a comparator product Vistabel/Botox containing botulinum toxin type A complex (onabotulinumtoxin A, 900 kD) was shown in two comparative, prospective, multicentre, randomised, double-blind studies (n=631) using single-doses (20 and 24 units, respectively). Study results demonstrated that XEOMIN and the comparator product have a similar efficacy and safety profile in patients with moderate to severe glabellar frown lines when used with a dosing conversion ratio of 1:1 (see section 4.2).

Long-term safety in repeat-dose (20 units) treatment of glabellar frown lines has been demonstrated in a Phase III study over a treatment period of up to two years with up to 8 consecutive injection cycles (MRZ 60201-0609, n=796) [Rzany et al., 2013].

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

General characteristics of the active substance
Classic kinetic and distribution studies cannot be conducted with botulinum neurotoxin type A because the active substance is applied in such small quantities (picograms per injection) and binds rapidly and irreversibly to the cholinergic nerve terminals.

Native botulinum toxin type A is a high molecular weight complex which, in addition to the neurotoxin (150 kD), contains other non-toxic proteins, like haemagglutinins and non- haemagglutinins. In contrast to conventional preparations containing the botulinum toxin type A complex, XEOMIN contains pure (150 kD) neurotoxin because it is free from complexing proteins and thus has a low foreign protein content. The foreign protein content administered is considered as one of the factors for secondary therapy failure.

Botulinum neurotoxin type A has been shown to undergo retrograde axonal transport after intramuscular injection. However, retrograde transsynaptic passage of active botulinum neurotoxin type A into the central nervous system has not been found at therapeutically relevant doses.

Receptor-bound botulinum neurotoxin type A is endocytosed into the nerve terminal prior to reaching its target (SNAP 25) and is then degraded intracellularly. Free circulating botulinum neurotoxin type A molecules, which have not bound to presynaptic cholinergic nerve terminal receptors, are phagocytosed or pinocytosed and degraded like any other free circulating protein.

Distribution of the active substance in patients
Human pharmacokinetic studies with XEOMIN have not been performed for the reasons detailed above.