June 27, 2016
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Dysport

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Dysport




CLINICAL PHARMACOLOGY

Mechanism Of Action

DYSPORT® inhibits release of the neurotransmitter, acetylcholine, from peripheral cholinergic nerve endings. Toxin activity occurs in the following sequence: Toxin heavy chain mediated binding to specific surface receptors on nerve endings, internalization of the toxin by receptor mediated endocytosis, pH-induced translocation of the toxin light chain to the cell cytosol and cleavage of SNAP25 leading to intracellular blockage of neurotransmitter exocytosis into the neuromuscular junction. This accounts for the therapeutic utility of the toxin in diseases characterized by excessive efferent activity in motor nerves.

Recovery of transmission occurs gradually as the neuromuscular junction recovers from SNAP25 cleavage and as new nerve endings are formed.

Pharmacodynamics

The primary pharmacodynamic effect of DYSPORT® is due to chemical denervation of the treated muscle resulting in a measurable decrease of the compound muscle action potential, causing a localized reduction of muscle activity.

Pharmacokinetics

Using currently available analytical technology, it is not possible to detect DYSPORT® in the peripheral blood following intramuscular injection at the recommended doses.

Clinical Studies

Cervical Dystonia

The efficacy of DYSPORT® was evaluated in two randomized, double-blind, placebo controlled, single dose, parallel group studies in treatment-na´ve cervical dystonia patients. The principal analyses from these trials provide the primary demonstration of efficacy involving 252 patients (121 on DYSPORT®, 131 on placebo) with 36% male and 64% female. Ninety-nine percent of the patients were Caucasian.

In both placebo controlled studies (Study 1 and Study 2), a dose of 500 Units DYSPORT® was given by intramuscular injection divided among two to four affected muscles. These studies were followed by long-term open label extensions that allowed titration in 250 Unit steps to doses in a range of 250 to 1000 Units, after the initial dose of 500 Units. In the extension studies, re-treatment was determined by clinical need after a minimum of 12 weeks. The median time to re-treatment was 14 weeks and 18 weeks for the 75th percentile.

The primary assessment of efficacy was based on the total Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) change from baseline at Week 4 for both studies. The scale evaluates the severity of dystonia, patient perceived disability from dystonia, and pain. The adjusted mean change from baseline in the TWSTRS total score was statistically significantly greater for the DYSPORT® group than the placebo group at Weeks 4 in both studies (see Table 7).

Table 7: TWSTRS Total Score Efficacy Outcome from the Phase 3 Cervical Dystonia Studies Intent to Treat Population

  Study 1 Study 2
DYSPORT® 500 Units
N=55
Placebo
N=61
DYSPORT® 500 Units
N=37
Placebo
N=43
Baseline (week 0)
Mean (SD) 43.8 (8.0) 45.8 (8.9) 45.1 (8.7) 46.2 (9.4)
Week 4
Mean (SD) 30.0 (12.7) 40.2 (11.8) 35.2 (13.8) 42.4 (12.2)
Change from Baselinea -15.6 (2.0) -6.7 (2.0) -9.6 (2.0) -3.7 (1.8)
Treatment difference 95% confidence interval -8.9* [-12.9 to -4.7] -5.9* [-10.6 to -1.3]
Week 8
Mean (SD) 29.3 (11.0) 39.6 (13.5)  
Change from Baselinea -14.7 (2.0) -5.9 (2.0)  
Treatment difference 95% confidence interval -8.8* [-12.9 to -4.7]  
a Change from baseline is expressed as adjusted least squares mean (SE)
*Significant at p-value < 0.05

Analyses by gender, weight, geographic region, underlying pain, cervical dystonia severity at baseline and history of treatment with botulinum toxin did not show any meaningful differences between groups.

Table 8 indicates the average DYSPORT® dose, and percentage of total dose, injected into specific muscles in the pivotal clinical trials.

Table 8: DYSPORT® 500 Units starting dose (units and % of the total dose) by Unilateral Muscle Injected During Double- blind Pivotal Phase 3 studies 2 and 1 Combined

Number of patients injected per musclea   DYSPORT® Dose Injected Percentage of the total DYSPORT® Dose Injected
Median [DYSPORT® Units] (min, max) 75th percentile [DYSPORT® Units] Median [%] (min, max) 75th percentile [%]
Sternocleidomastoid 90 125 Units (50, 350) 150 Units 26.5 % (10, 70) 30.0 %
Splenius capitis 85 200 Units (75, 450) 250 Units 40.0 % (15, 90) 50.0 %
Trapezius 50 102.6 Units (50, 300) 150 Units 20.6 % (10, 60) 30.0 %
Levator scapulae 35 105.3 Units (50, 200) 125 Units 21.1 % (10, 40) 25.0 %
Scalenus (medius and anterior) 26 115.5 Units (50, 300) 150 Units 23.1 % (10, 60) 30.0 %
Semispinalis capitis 21 131.6 Units (50, 250) 175 Units 29.4 % (10, 50) 35.0 %
Longissimus 3 150 Units (100, 200) 200 Units 30.0 % (20, 40) 40.0 %
a Total number of patients in combined studies 2 and 1 who received initial treatment = 121.

Glabellar Lines

Three double-blind, randomized, placebo-controlled, clinical studies evaluated the efficacy of DYSPORT® for use in the temporary improvement of the appearance of moderate to severe glabellar lines. These three studies enrolled healthy adults (ages 19-75) with glabellar lines of at least moderate severity at maximum frown. Subjects were excluded if they had marked ptosis, deep dermal scarring, or a substantial inability to lessen glabellar lines, even by physically spreading them apart. The subjects in these studies received either DYSPORT® or placebo. The total dose was delivered in equally divided aliquots to specified injection sites (see Figure 1).

Investigators and subjects assessed efficacy at maximum frown by using a 4-point scale (none, mild, moderate, severe).

Overall treatment success was defined as post-treatment glabellar line severity of none or mild with at least 2 grade improvement from Baseline for the combined investigator and subject assessments (composite assessment) on Day 30 (see Table 9). Additional endpoints for each of the studies were post-treatment glabellar line severity of none or mild with at least a 1 grade improvement from Baseline for the separate investigator and subject assessments on Day 30.

After completion of the randomized studies, subjects were offered participation in a two-year, open-label re-treatment study to assess the safety of multiple treatments.

Table 9: Treatment Success at Day 30 (None or Mild with at least 2 Grade Improvement from Baseline at Maximum Frown for the combined Investigator and Subject Assessments (Composite))

Study 2 Grade Improvement
DYSPORT®
n/N (%)
Placebo
n/N (%)
GL-1 58/105 (55%) 0/53 (0%)
GL-2 37/71 (52%) 0/71 (0%)
GL-3 120/200 (60%) 0/100 (0%)

Treatment with DYSPORT® reduced the severity of glabellar lines for up to four months.

Study GL-1

Study GL-1 was a single dose, double-blind, multi-center, randomized, placebo-controlled study in which 158 previously untreated subjects received either placebo or 50 Units of DYSPORT®, administered in five aliquots of 10 Units (see Figure 1). Subjects were followed for 180 days. The mean age was 43 years; most of the subjects were women (85%), and predominantly Caucasian (49%) or Hispanic (47%). At Day 30, 55% of DYSPORT®-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (Table 9).

In study GL-1, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT® group compared to the placebo group as assessed by both Investigators and subjects (Table 10).

Table 10: GL-1: Investigator's and Subject's Assessment of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)

Day Investigator’s Assessment Subject’s Assessment
DYSPORT®
N=105
Placebo
N=53
DYSPORT®
N=105
Placebo
N=53
14 90% 17% 77% 9%
95 9 81 5
30 88% 4% 74% 9%
92 2 78 5
60 64% 2% 60% 6%
67 1 63 3
90 43% 6% 36% 6%
45 3 38 3
120 23% 4% 19% 6%
24 2 20 3
150 9% 2% 8% 4%
9 1 8 2
180 6% 0% 7% 8%
6 0 7 4

Study GL-2

Study GL-2 was a repeat dose, double-blind, multi-center, placebo-controlled, randomized study. The study was initiated with two or three open-label treatment cycles of 50 Units of DYSPORT® administered in five aliquots of 10 Units DYSPORT® (see Figure 1). After the open-label treatments, subjects were randomized to receive either placebo or 50 Units of DYSPORT®. Subjects could have received up to four treatments through the course of the study. Efficacy was assessed in the final randomized treatment cycle. The study enrolled 311 subjects into the first treatment cycle and 142 subjects were randomized into the final treatment cycle. Overall, the mean age was 47 years; most of the subjects were women (86%) and predominantly Caucasian (80%).

At Day 30, 52% of DYSPORT®-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 9).

The proportion of responders in the final treatment cycle was comparable to the proportion of responders in all prior treatment cycles. After the final repeat treatment with DYSPORT®, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT® group compared to the placebo group as assessed by both Investigators and subjects (Table 12).

Table 11: GL-2: Investigator's and Subject's Assessments of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)

Day Investigator’s Assessment Subject’s Assessment
DYSPORT®
N=71
Placebo
N=71
DYSPORT®
N=71
Placebo
N=71
30 85% 4% 79% 1%
60 3 56 1

Study GL-3

Study GL-3 was a single dose, double-blind, multi-center, randomized, placebo-controlled study in which 300 previously untreated subjects received either placebo or 50 Units of DYSPORT®, administered in five aliquots of 10 Units (see Figure 1). Subjects were followed for 150 days. The mean age was 44 years; most of the subjects were women (87%), and predominantly Caucasian (75%) or Hispanic (18%).

At Day 30, 60% of DYSPORT®-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 9).

In study GL-3, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT® group compared to the placebo group as assessed by both Investigators and subjects (see Table 12).

Table 12: GL-3: Investigator's and Subject's Assessment of Glabellar Line Severity at Maximum Frown Using a 4-point Scale (% and Number of Subjects with Severity of None or Mild)

Day Investigator’s Assessment Subject’s Assessment
DYSPORT®
N=200
Placebo
N=100
DYSPORT®
N=200
Placebo
N=100
14 83% 5% 83% 2%
166 5 165 2
30 86% 0% 82% 2%
171 0 163 2
60 75% 1% 65% 4%
150 1 130 4
90 51% 1% 46% 2%
102 1 91 2
120 29% 1% 31% 3%
58 1 61 3
150 16% 1% 16% 3%
32 1 31 3

Geriatric Subjects

In GL1, GL2, and GL3, there were 8 subjects aged 65 and older who were randomized to DYSPORT® 50 Units in 5 equal aliquots of 10 Units (4) or placebo (4). None of the geriatric DYSPORT® subjects were a treatment success at maximum frown at Day 30.

Upper Limb Spasticity

The efficacy and safety of DYSPORT® for the treatment of upper limb spasticity was evaluated in a randomized, multi-center, double- blind, placebo-controlled study that included 238 patients (159 DYSPORT® and 79 placebo) with upper limb spasticity (Modified Ashworth Scale (MAS) score ≥ 2 in the primary targeted muscle group for toxin naive patients or MAS score ≥ 3 in the primary targeted muscle group for toxin non-naive patients at least 4 months after the last botulinum toxin injection, of any serotype) who were at least 6 months post-stroke or post-traumatic brain injury.

DYSPORT® 500 Units (N=80), DYSPORT® 1000 Units (N=79), or placebo (N=79) was injected intramuscularly into the affected upper limb muscles. After injection of the primary targeted muscle groups (PTMG), the remainder of the dose was injected into at least two additional upper limb muscles determined by the patient's individual presentation. Table 13 provides the mean and range of DYSPORT® doses injected and the number of injections into specific muscles of the upper limb.

Table 13 :DYSPORT® Dose Injected and Number of Injections per Muscle

Muscle DYSPORT® Treatment Group Number of Patients Mean DYSPORT® Units Injected (Min, Max) Number Of Injection Sites Median, [Q1 ; Q3]
Flexor digitorum profundus (FDP)* 500 U 54 93.5 Units (50 to 100) 1, [1 ; 2]
1000 U 65 195.5 Units (100 to 300) 2, [1 ; 2]
Flexor digitorum superficialis (FDS)* 500 U 63 95.4 Units (50 to 100) 2, [1 ; 2]
1000 U 73 196.8 Units (100 to 300) 2, [1 ; 2]
Flexor carpi radialis (FCR)* 500 U 57 92.2 Units (25 to 100) 1, [1 ; 2]
1000 U 57 178.1 Units (80 to 300) 1, [1 ; 2]
Flexor carpi ulnaris (FCU)* 500 U 47 89.9 Units (25 to 180) 1, [1 ; 2]
1000 U 49 171.2 Units (80 to 200) 1, [1 ; 2]
Brachialis* 500 U 60 148.5 Units (50 to 200) 2, [1 ; 2]
1000 U 43 321.4 Units (100 to 400) 2, [2 ; 2]
Brachioradialis* 500 U 42 88.3 Units (50 to 200) 1, [1 ; 2]
1000 U 28 172.1 Units (50 to 200) 1, [1 ; 2]
Biceps Brachii (BB) 500 U 28 106.4 Units (50 to 200) 2, [1 ; 2]
1000 U 19 207.4 Units (100 to 400) 2, [1 ; 2]
Pronator Teres 500 U 14 81.8 Units (45 to 200) 1, [1 ; 1]
1000 U 30 157.3 Units (80 to 200) 1, [1 ; 1]
*PTMG

The co-primary efficacy variables were muscle tone assessed by the MAS at the primary targeted muscle group at week 4 and the Physician Global Assessment (PGA) at week 4.

Table 14 : Primary Endpoints (PTMG MAS and PGA) and MAS by Muscle Group at Week 4

  Placebo
(N=79)
DYSPORT®
(500 units)
(N=80)
(1000 units)
(N=79)
LS Mean Change from Baseline in PTMG Muscle Tone on the MAS -0.3 -1.2* -1.4*
LS Mean PGA of Response to Treatment 0.7 1.4* 1.8*
LS Mean Change from Baseline in Wrist Flexor Muscle Tone on the MAS -0.3 (n=54) -1.4 (n=57) -1.6 (n=58)
LS Mean Change from Baseline in Finger Flexor Muscle Tone on the MAS -0.3 (n=70) -0.9 (n=66) -1.2 (n=73)
LS Mean Change from Baseline in Elbow Flexor Muscle Tone on the MAS -0.3 (n=56) -1.0 (n=61) -1.2 (n=48)
LS= Least Square;
*p ≤ 0.05

Last reviewed on RxList: 3/17/2016
This monograph has been modified to include the generic and brand name in many instances.

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