Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other Muscle relaxants, peripherally acting agents ATC code: M03A X01.

Mechanism of action
Botulinum toxin type A blocks peripheral acetylcholine release at presynaptic cholinergic nerve terminals by cleaving SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within the nerve endings.

Pharmacodynamic effect
After injection, there is an initial rapid high-affinity binding of toxin to specific cell surface receptors.
This is followed by transfer of the toxin across the plasma membrane by receptor-mediated endocytosis. Finally, the toxin is released into the cytosol. This latter process is accompanied by progressive inhibition of acetylcholine release, clinical signs are manifest within 2-3 days, with peak effect seen within 5-6 weeks of injection. Clinical evidence suggests that BOTOX reduces pain and neurogenic inflammation and elevates cutaneous heat pain thresholds in a capsaicin induced trigeminal sensitization model.

Recovery after intramuscular injection takes place normally within 12 weeks of injection as nerve terminals sprout and reconnect with the endplates. After intradermal injection, where the target is the eccrine sweat glands the effect lasted an average of 7.5 months after the first injection in patients treated with 50 Units per axilla. However, in 27.5 % of patients the duration of effect was 1 year or greater. Recovery of sympathetic nerve endings that innervate sweat glands after intradermal injection with BOTOX has not been studied.

Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release. In addition BOTOX may inhibit afferent neurotransmitters and sensory pathways.

Clinical efficacy and safety

NEUROLOGIC DISORDERS
Focal lower limb spasticity associated with stroke in adults

The efficacy and safety of BOTOX for the treatment of lower limb spasticity was evaluated in a randomized, multi-center, double-blind, placebo-controlled study which included 468 post-stroke patients (233 BOTOX and 235 placebo) with ankle spasticity (Modified Ashworth Scale [MAS] ankle score of at least 3) who were at least 3 months post-stroke. BOTOX 300 to 400 Units or placebo were injected intramuscularly into the study mandatory muscles gastrocnemius, soleus, and tibialis posterior and optional muscles including flexor hallucis longus, flexor digitorum longus, flexor digitorum brevis, extensor hallucis, and rectus femoris.

The primary endpoint was the average change from baseline of weeks 4 and 6 MAS ankle score and a key secondary endpoint was the average CGI (Physician Global Assessment of Response) at weeks 4 and 6. Statistically and clinically significant between-group differences for BOTOX over placebo were demonstrated for the primary efficacy measures of MAS and key secondary measure of CGI and are 
BOT API MAR23 CL-2                                 30/44
presented in table below. For the primary endpoint of average MAS ankle score at weeks 4 and 6, no improvement from baseline was observed for patients aged 65 and older in the BOTOX group compared to placebo, likely due to small patient numbers.

Primary and Key Secondary Efficacy Endpoints

BOTOX®        Placebo
300 to 400
Units (ITT)    (N=235)
(N=233)
Mean Changes from Baseline in Ankle Plantar Flexors in
MAS Score
Week 4 and 6 Average                                          -0.8*       -0.6 Mean Clinical Global Impression Score by Investigator
Week 4 and 6 Average                                           0.9*         0.7 Mean Change in Toe Flexors in MAS Score
FHaL Week 4 and 6 Average                                  -1.02*           -0.6 FDL Week 4 and 6 Average                                    -0.88          - 0.77 Mean Change from Baseline in Ankle Plantar Flexors in           ≥65 years      ≥65 years MAS Score for Patients                                            N=60           N=64 Week 4 and 6 Average                                         -0.7           -0.7 *Significantly different from placebo (p<0.05)

Another double-blind, placebo-controlled, randomised, multi-centre, Phase 3 clinical study was conducted in adult post stroke patients with lower limb spasticity affecting the ankle. A total of 120 patients were randomised to receive either BOTOX (n=58) (total dose of 300 Units) or placebo (n=62). This study was conducted exclusively in Japanese patients with Modified Ashworth Scale (MAS) ≥ 3 who were on average 6.5 years post-stroke.

Significant improvement compared to placebo was observed in the primary endpoint for the overall change from baseline up to week 12 in the MAS ankle score, which was calculated using the area under the curve (AUC) approach. Significant improvements compared to placebo were also observed for the mean change from baseline in MAS ankle score at individual post-treatment visits at weeks 4, 6 and 8. The proportion of responders (patients with at least a 1 grade improvement) was also significantly higher than in placebo treated patients at these visits.

BOTOX treatment was also associated with significant improvement in the investigator’s clinical global impression (CGI) of functional disability (secondary endpoint, no multiplicity adjustment) compared to placebo. There was no clinically meaningful improvement in function as measured by the Physician’s Rating Scale (PRS) and speed of gait.

Results from the phase 3 study are presented below.

Primary and Key Secondary Efficacy Endpoints
BOTOX                Placebo           p-value
(N=58)               (N=62)
Mean AUC in MAS Score
AUC (day 0 to week 12)                 -8.5                -5.1              0.006 Mean Change from Baseline in
MAS Score
Baseline                               3.28               3.24
Week 1                                -0.61               -0.52             0.222 Week 4                                -0.88               -0.43            < 0.001 

BOT API MAR23 CL-2                                 31/44
Week 6                                  -0.91                 -0.47           < 0.001 Week 8                                  -0.82                 -0.43           < 0.001 Week 12                                 -0.56                 -0.40               0.240 Percentage of Responders*
Week 1                                  52.6%                38.7%             0.128 Week 4                                  67.9%                30.6%            < 0.001 Week 6                                  68.4%                36.1%            < 0.001 Week 8                                  66.7%                32.8%            < 0.001 Week 12                                 44.4%                34.4%             0.272 *Patients   with at least a 1 grade improvement from baseline in MAS score 
A consistent response was observed with re-treatment.

Chronic migraine
BOTOX blocks the release of neurotransmitters associated with the genesis of pain. The mechanism of action of BOTOX for symptom relief in chronic migraine is not fully established. Pre-clinical and clinical pharmacodynamic studies suggest that BOTOX suppresses peripheral sensitisation, thereby possibly also inhibiting central sensitisation.
The main results achieved from the pooled efficacy analysis after two BOTOX treatments administered at a 12-week interval from two phase 3 clinical trials in chronic migraine patients, who during a 28-day baseline period had at least 4 episodes and ≥ 15 headache days (with at least 4 hours of continuous headache), with at least 50% of headache days being migraine/probable migraine days, are shown in the table below:

Mean change from baseline at Week 24                         BOTOX        Placebo        p-value N=688        N=696
Frequency of headache days                                   -8.4         -6.6           p<0.001 Frequency of moderate/severe headache days                   -7.7         -5.8           p<0.001 Frequency of migraine/probable migraine days                 -8.2         -6.2           p<0.001 % patients with 50% reduction in headache days               47%          35%            p<0.001 Total cumulative hours of headache on headache               -120         -80            p<0.001 days
Frequency of headache episodes                               -5.2         -4.9           p=0.009 Total Headache Impact Test (HIT-6) scores                    -4.8         -2.4           p<0.001 
Although the studies were not powered to show differences in subgroups, the treatment effect appeared smaller in the subgroup of male patients (N=188) and non-Caucasians (N= 137) than in the whole study population.

Strabismus
When used for the treatment of strabismus, it has been postulated that the administration of BOTOX affects muscle pairs by inducing an atrophic lengthening of the injected muscle and a corresponding shortening of the antagonist muscle. In an open trial, 677 patients with strabismus were treated with one or more injections of BOTOX. Fifty-five percent (55%) of these patients were improved to an alignment of 10 prism diopters or less when evaluated six months or more following injection. These results are consistent with results from additional open label trials which were conducted for this indication.

BLADDER DISORDERS

Overactive bladder
Two double-blind, placebo-controlled, randomised, multi-centre, 24 week Phase 3 clinical studies were conducted in patients with overactive bladder with symptoms of urinary incontinence, urgency and frequency. A total of 1105 patients, whose symptoms had not been adequately managed with at 
BOT API MAR23 CL-2                                    32/44
least one anticholinergic therapy (inadequate response or intolerable side effects), were randomised to receive either 100 Units of BOTOX (n=557), or placebo (n=548).

In both studies, significant improvements compared to placebo in the change from baseline in daily frequency of urinary incontinence episodes were observed for BOTOX (100 Units) at the primary time point of week 12 (baseline was 5.49 for BOTOX and 5.39 for placebo), including the proportion of dry patients. Using the Treatment Benefit Scale, the proportion of patients reporting a positive treatment response (their condition had been ‘greatly improved’ or ‘improved’) was significantly greater in the BOTOX group compared to the placebo group in both studies. Significant improvements compared to placebo were also observed for the daily frequency of micturition, urgency and nocturia episodes.
Volume voided per micturition was also significantly higher. Significant improvements were observed in all overactive bladder symptoms from week 2.

BOTOX treatment was associated with significant improvements over placebo in health-related quality of life as measured by the Incontinence Quality of Life (I-QOL) questionnaire (including avoidance and limiting behaviour, psychosocial impact and social embarrassment), and the King’s Health Questionnaire (KHQ) (including incontinence impact, role limitations, social limitations, physical limitations, personal relationships, emotions, sleep/energy and severity/coping measures).
No overall difference in effectiveness following BOTOX treatment was observed between patients ≥65 years compared to <65 years.

Results from the pooled pivotal studies are presented below:

Primary and Secondary Efficacy Endpoints at Baseline and Change from Baseline in the Pooled Pivotal Studies:



BOT API MAR23 CL-2                              33/44
BOTOX            Placebo          p-value
100 Units        (N=548)
(N=557)
Daily Frequency of Urinary Incontinence
Episodes*
Mean Baseline                             5.49             5.39
Mean Change at Week 2                     -2.85            -1.21          < 0.001 Mean Change at Week 6                     -3.11            -1.22          < 0.001 Mean Change at Week 12a                   -2.80            -0.95          < 0.001 Proportion with Positive Treatment
Response using Treatment Benefit Scale
(%)
Week 2                                     64.4            34.7           < 0.001 Week 6                                     68.1            32.8           < 0.001 Week 12a                                   61.8            28.0           < 0.001 Daily Frequency of Micturition Episodes
Mean Baseline                             11.99            11.48
Mean Change at Week 2                     -1.53            -0.78          < 0.001 Mean Change at Week 6                     -2.18            -0.97          < 0.001 Mean Change at Week 12b                   -2.35            -0.87          < 0.001 Daily Frequency of Urgency Episodes
Mean Baseline                             8.82             8.31
Mean Change at Week 2                     -2.89            -1.35          < 0.001 Mean Change at Week 6                     -3.56            -1.40          < 0.001 Mean Change at Week 12b                   -3.30            -1.23          < 0.001 Incontinence Quality of Life Total Score
Mean Baseline                              34.1            34.7
Mean Change at Week 12bc                  +22.5            +6.6           < 0.001 King’s Health Questionnaire: Role
Limitation
Mean Baseline                             65.4             61.2
Mean Change at Week 12bc                  -25.4            -3.7           < 0.001 King’s Health Questionnaire: Social
Limitation
Mean Baseline                             44.8             42.4
Mean Change at Week 12bc                  -16.8            -2.5           < 0.001 * Percentage of patients who were dry (without incontinence) at week 12 was 27.1% for the BOTOX group and 8.4% for the placebo group. The proportions achieving at least a 75% and 50% reduction from baseline in urinary incontinence episodes were 46.0% and 60.5% in the BOTOX group compared to 17.7% and 31.0% in the placebo group, respectively.
a
Co-primary endpoints b
Secondary endpoints c
Pre-defined minimally important change from baseline was +10 points for I-QOL and -5 points for KHQ

The median duration of response following BOTOX treatment, based on patient request for re- treatment, was 166 days (~24 weeks). The median duration of response, based on patient request for re-treatment, in patients who continued into the open label extension study and received treatments with only BOTOX 100 Units (N=438), was 212 days (~30 weeks).

Although only a limited number of patients aged <40 years (n=88, 8.0%), non-Caucasians (n=101, 9.1%) and males (n=135, 12.2%) were studied in the two Phase 3 clinical studies, data in these subgroups were supportive of a positive treatment effect. A higher incidence of the adverse events of urinary retention, residual urine volume, and pollakiuria was observed in males compared to females.
Results for the co-primary endpoints in males are presented below:

Co-primary Efficacy Endpoints at Baseline and Change from Baseline in Male Patients (Pooled Pivotal Studies):


BOT API MAR23 CL-2                             34/44
BOTOX             Placebo          p-value
100 Units         (N=74)
(N=61)
Daily Frequency of Urinary Incontinence
Episodes
Mean Baseline                              5.61             4.33
Mean Change at Week 12                     -1.86            -1.23            0.612 Proportion with Positive Treatment
Response using Treatment Benefit Scale
(%)
Week 12                                     40.7             25.4            0.060 
A total of 839 patients were evaluated in a long-term open-label extension study (n=758 females, n=81 males). For all efficacy endpoints, patients experienced consistent response with re-treatments. In the subset of 345 patients (n=316 females, n=29 males), who had reached week 12 of treatment cycle 3, the mean reductions in daily frequency of urinary incontinence were -3.07, -3.49, and -3.49 episodes at week 12 after the first, second, and third BOTOX 100 Unit treatments, respectively. The corresponding proportions of patients with a positive treatment response on the Treatment Benefit Scale were 63.6%, 76.9%, and 77.3%, respectively.

In the pivotal studies, none of the 615 patients with analysed specimens developed neutralising antibodies. In patients with analysed specimens from the pivotal phase 3 and the open-label extension studies, neutralising antibodies developed in 0 of 954 patients (0.0%) while receiving BOTOX 100 Unit doses and 3 of 260 patients (1.2%) after subsequently receiving at least one 150 Unit dose. One of these three patients continued to experience clinical benefit. Compared to the overall BOTOX treated population, patients who developed neutralising antibodies generally had shorter duration of response and consequently received treatments more frequently (see section 4.4).

Adult urinary incontinence due to neurogenic detrusor overactivity

Pivotal Phase 3 Clinical Trials
Two double-blind, placebo-controlled, randomised, multi-centre Phase 3 clinical studies were conducted in patients with urinary incontinence due to neurogenic detrusor overactivity who were either spontaneously voiding or using catheterisation. A total of 691 spinal cord injury or multiple sclerosis patients, not adequately managed with at least one anticholinergic agent, were enrolled.
These patients were randomised to receive either 200 Units of BOTOX (n=227), 300 Units of BOTOX (n=223), or placebo (n=241).

In both phase 3 studies, significant improvements compared to placebo in the primary efficacy variable of change from baseline in weekly frequency of incontinence episodes were observed favouring BOTOX (200 Units and 300 Units) at the primary efficacy time point at week 6, including the percentage of dry patients. Significant improvements in urodynamic parameters including increase in maximum cystometric capacity and decreases in peak detrusor pressure during the first involuntary detrusor contraction were observed. Significant improvements, compared with placebo, in patient reported incontinence specific health-related quality of life scores as measured by the I-QOL (including avoidance limiting behaviour, psychosocial impact and social embarrassment) were also observed. No additional benefit of BOTOX 300 Units over 200 Units was demonstrated and a more favourable safety profile was observed with BOTOX 200 Units.



BOT API MAR23 CL-2                              35/44
Results from the pooled pivotal studies are presented below:

Primary and Secondary Endpoints at Baseline and Change from Baseline                    in Pooled Pivotal Studies:
BOTOX       Placebo                         p-value
200 Units   (N=241)
(N=227)
Weekly Frequency of Urinary Incontinence*
Mean Baseline                           32.4        31.5
Mean Change at Week 2                   -17.7       -9.0                         p<0.001 Mean Change at Week 6a                  -21.3      -10.5                         p<0.001 Mean Change at Week 12                  -20.6       -9.9                         p<0.001 Maximum Cystometric Capacity (ml)
Mean Baseline                           250.2      253.5
Mean Change at Week 6b                 +153.6      +11.9                         p<0.001 Maximum Detrusor Pressure during 1st
Involuntary Detrusor Contraction (cmH20)
Mean Baseline                           51.5        47.3
Mean Change at Week 6b                  -32.4      +1.1                          p<0.001 Incontinence Quality of Life Total Scorec,d
Mean Baseline                           35.37      35.32
Mean Change at Week 6b                 +25.89     +11. 15                        p<0.001 Mean Change at Week 12                 +28.89      +8.86                         p<0.001 * Percentage of dry patients (without incontinence) throughout week 6 was 37% for the 200 Unit BOTOX group and 9% for placebo. The proportions achieving at least a 75% reduction from baseline, in incontinence episodes, were 63% and 24% respectively. The proportions achieving at least a 50% reduction from baseline were 76% and 39% respectively.
a
Primary endpoint b
Secondary endpoints c
I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all ).
d
In the pivotal studies, the pre-specified minimally important difference (MID) for I-QOL total score was 8 points based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.

The median duration of response in the two pivotal studies, based on patient request for re-treatment, was 256-295 days (36-42 weeks) for the 200 Unit dose group compared to 92 days (13 weeks) with placebo. The median duration of response, based on patient request for re-treatment, in patients who continued into the open label extension study and received treatments with only BOTOX 200 Units (N=174), was 253 days (~36 weeks).

For all efficacy endpoints, patients experienced consistent response with re-treatment.

In the pivotal studies, none of the 475 neurogenic detrusor overactivity patients with analysed specimens developed neutralising antibodies. In patients with analysed specimens in the drug development program (including the open-label extension study), neutralising antibodies developed in 3 of 300 patients (1.0%) after receiving only BOTOX 200 Unit doses and 5 of 258 patients (1.9%) after receiving at least one 300 Unit dose. Four of these eight patients continued to experience clinical benefit. Compared to the overall BOTOX treated population, patients who developed neutralising antibodies generally had shorter duration of response and consequently received treatments more frequently (see section 4.4).

Post-approval Study
A placebo controlled, double-blind post-approval study was conducted in multiple sclerosis (MS) patients with urinary incontinence due to neurogenic detrusor overactivity who were not adequately managed with at least one anticholinergic agent and not catheterising at baseline. These patients were randomised to receive either 100 Units of BOTOX (n=66) or placebo (n=78).

BOT API MAR23 CL-2                                 36/44
Significant improvements compared to placebo in the primary efficacy variable of change from baseline in daily frequency of incontinence episodes were observed for BOTOX (100 Units) at the primary efficacy time point at week 6, including the percentage of dry patients. Significant improvements in urodynamic parameters, and Incontinence Quality of Life questionnaire (I-QOL), including avoidance limiting behaviour, psychosocial impact and social embarrassment were also observed.

Results from the post-approval study are presented below:

Primary and Secondary Endpoints at Baseline and Change from Baseline in Post-Approval Study of BOTOX 100 Units in MS patients not catheterising at baseline: 
BOTOX       Placebo        p-values
100 Units   (N=78)
(N=66)
Daily      Frequency        of     Urinary
Incontinence*
Mean Baseline                                4.2         4.3
Mean Change at Week 2                        -2.9        -1.2           p<0.001 a
Mean Change at Week 6                        -3.3        -1.1           p<0.001 Mean Change at Week 12                       -2.8        -1.1           p<0.001 Maximum Cystometric Capacity (mL)
Mean Baseline                                246.4       245.7
Mean Change at Week 6b                       +127.2      -1.8           p<0.001 Maximum Detrusor Pressure during 1st
Involuntary      Detrusor      Contraction
(cmH2O)
Mean Baseline                                35.9        36.1
Mean Change at Week 6b                       -19.6       +3.7           p=0.007 Incontinence Quality of Life Total
Scorec,d
Mean Baseline                                32.4        34.2
Mean Change at Week 6b                       +40.4       +9.9           p<0.001 Mean Change at Week 12                       +38.8       +7.6           p<0.001 * Percentage of dry patients (without incontinence) throughout week 6 was 53.0% (100 Unit BOTOX group) and 10.3% (placebo) a
Primary endpoint b
Secondary endpoints c
I-QOL total score scale ranges from 0 (maximum problem) to 100 (no problem at all).
d
The pre-specified minimally important difference (MID) for I-QOL total score was 11 points based on MID estimates of 4-11 points reported in neurogenic detrusor overactivity patients.

The median duration of response in this study, based on patient request for re-treatment, was 362 days (~52 weeks) for BOTOX 100 Unit dose group compared to 88 days (~13 weeks) with placebo.

SKIN AND SKIN APPENDAGE DISORDER

Primary hyperhidrosis of the axillae
A double-blind, multi-centre clinical study was conducted in patients presenting with persistent bilateral primary axillary hyperhidrosis defined as baseline gravimetric measurement of at least 50 mg spontaneous sweat production in each axilla over 5 minutes at room temperature, at rest. Three hundred and twenty patients were randomised to receive either 50 Units of BOTOX (n=242) or placebo (n=78). Treatment responders were defined as subjects showing at least a 50% reduction from baseline in axillary sweating. At the primary endpoint, week 4 post-injection, the response rate in the 
BOT API MAR23 CL-2                              37/44
BOTOX group was 93.8% compared with 35.9% in the placebo group (p 0.001). The incidence of responders among BOTOX treated patients continued to be significantly higher (p<0.001) than placebo treated patients at all post-treatment time points for up to 16 weeks.

A follow up open-label study enrolled 207 eligible patients who received up to 3 BOTOX treatments.
Overall, 174 patients completed the full 16-month duration of the 2 studies combined (4 month double-blind and 12 month open-label continuation). Incidence of clinical response at week 16 following the first (n=287), second (n=123) and third (n=30) treatments was 85.0%, 86.2% and 80% respectively. The mean duration of effect based on the combined single-dose and open-label continuation trial was 7.5 months following the first treatment, however for 27.5% of patients the duration of effect was 1 year or greater.

There is limited clinical trial experience of the use of BOTOX in primary axillary hyperhidrosis in children between the ages of 12 and 18. A single, year long, uncontrolled, repeat dose, safety study was conducted in US paediatric patients 12 to 17 years of age (n=144) with severe primary hyperhidrosis of the axillae. Participants were primarily female (86.1%) and Caucasian (82.6%).
Participants were treated with a dose of 50 Units per axilla for a total dose of 100 Units per patient per treatment. However no dose finding studies have been conducted in adolescents so no recommendation on posology can be made. Efficacy and safety of BOTOX in this group have not been conclusively established.


Glabellar Lines
537 patients with moderate to severe glabellar lines seen at maximum frown have been included in clinical studies.

BOTOX injections significantly reduced the severity of glabellar lines seen at maximum frown for up to 4 months, as measured by the investigator assessment of glabellar line severity at maximum frown and by subject’s global assessment of change in appearance of his/her glabellar linesseen at maximum frown. None of the clinical endpoints included an objective evaluation of the psychological impact.
Thirty days after injection 80% (325/405) of BOTOX-treated patients were considered by investigators as treatment responders (none or mild severity at maximum frown), compared to 3% (4/132) of placebo-treated patients. At this same timepoint, 89% (362/405) of BOTOX-treated patients felt they had a moderate or better improvement, compared to 7% (9/132) of placebo-treated patients.
BOTOX injections also significantly reduced the severity of glabellar lines at rest. Of the 537 patients enrolled, 39% (210/537) had moderate to severe glabellar lines at rest (15% had no lines at rest). Of these, 74% (119/161) of BOTOX-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 20% (10/49) of placebo-treated patients.
There is limited phase 3 clinical data with BOTOX in patients older than 65 years. Only 6.0% (32/537) of subjects were >65 years old and efficacy results obtained were lower in this population.

Crow’s Feet Lines
1362 patients with moderate to severe crow’s feet lines seen at maximum smile, either alone (n=445, Study 191622-098) or also with moderate to severe glabellar lines seen at maximum frown (n=917, Study 191622-099), were enrolled.

BOTOX injections significantly reduced the severity of crow’s feet lines seen at maximum smile compared to placebo at all timepoints (p <0.001) for up to 5 months. This was measured by the proportion of patients achieving a crow’s feet lines severity rating of none or mild at maximum smile in both pivotal studies; until day 150 (end of study) in Study 191622-098 and day 120 (end of first treatment cycle in Study 191622-099). For both investigator and subject assessments, the proportion of subjects achieving none or mild crow’s feet lines severity seen at maximum smile was greater in patients with moderate crow’s feet lines seen at maximum smile at baseline, compared to patients with severe crow’s feet lines seen at maximum smile at baseline. Table 1 summarises results at day 30, the timepoint of the primary efficacy endpoint.


BOT API MAR23 CL-2                                38/44
In Study 191622-104 (extension to Study 191622-099), 101 patients previously randomised to placebo were enrolled to receive their first treatment at the 44 U dose. Patients treated with BOTOX had a statistically significant benefit in the primary efficacy endpoint compared to placebo at day 30 following their first active treatment. The response rate was similar to the 44 U group at day 30 following first treatment in Study 191622-099. A total of 123 patients received 4 cycles of 44 U BOTOX for combined crow’s feet and glabellar lines treatment.

Table 1. Day 30: Investigator and Patient Assessment of Crow’s Feet Lines Seen at Maximum Smile - Responder Rates (% of Patients Achieving Crow’s Feet Lines Severity Rating of None or Mild) 
Clinical       Dose                        BOTOX          Placebo         BOTOX          Placebo Study
Investigator Assessment        Patient Assessment
191622-098     24 U                        66.7%*         6.7%            58.1%*        5.4% (crow’s feet lines)         (148/222)      (15/223)        (129/222)     (12/223) 191622-099     24 U                        54.9%*         3.3%            45.8%*        3.3% (crow’s feet lines)         (168/306)      (10/306)        (140/306)     (10/306) 
44 U                         59.0%*         3.3%            48.5%*         3.3%
(24 U crow’s feet lines;     (180/305)      (10/306)        (148/305)      (10/306)               20 U glabellar lines)
*p < 0.001 (BOTOX vs placebo)

Improvements from baseline in subject assessment of the appearance of crow’s feet lines at maximum smile were seen for BOTOX (24 U and 44 U) compared to placebo, at day 30 and at all timepoints following each treatment cycle in both pivotal studies (p < 0.001).

Treatment with BOTOX 24 U also significantly reduced the severity of crow’s feet lines at rest. Of the 528 patients treated, 63% (330/528) had moderate to severe crow’s feet lines at rest at baseline. Of these, 58% (192/330) of BOTOX-treated patients were considered treatment responders (none or mild severity) thirty days after injection, compared with 11% (39/352) of placebo-treated patients.

Improvements in subjects’ self-assessment of age and attractiveness were also seen for BOTOX (24 U and 44 U) compared to placebo using the Facial Line Outcomes (FLO-11) questionnaire at the primary timepoint of day 30 (p<0.001) and at all subsequent timepoints in both pivotal studies.

In the pivotal studies, 3.9% (53/1362) of patients were older than 65 years of age. Patients in this age group had a treatment response as assessed by the investigator, of 36% (at day 30) for BOTOX (24 U and 44 U). When analyzed by age groups of ≤50 years and >50 years, both populations demonstrated statistically significant improvements compared to placebo. Treatment response for BOTOX 24 U, as assessed by the investigator, was lower in the group of subjects >50 years of age than those ≤50 years of age (42.0% and 71.2%, respectively).

Overall BOTOX treatment response for crow’s feet lines seen at maximum smile is lower (60%) than that observed with treatment for glabellar lines seen at maximum frown (80%).

916 patients (517 patients at 24 U and 399 patients at 44 U) treated with BOTOX had specimens analysed for antibody formation. No patients developed the presence of neutralising antibodies.

Forehead Lines
822 patients with moderate to severe forehead lines and glabellar lines seen at maximum contraction, either alone (N=254, Study 191622-142) or also with moderate to severe crow’s feet lines seen at maximum smile (N=568, Study 191622-143), were enrolled and included in the primary populations for analyses of all primary and secondary efficacy endpoints. In the clinical studies forehead lines were treated in conjugation with glabellar lines.

BOT API MAR23 CL-2                               39/44
For both investigator and patient assessments, the proportion of patients achieving none or mild forehead lines seen at maximum eyebrow elevation following BOTOX injections was greater than patients treated with placebo at day 30, the timepoint of the primary efficacy endpoint (Table 2). The proportions of patients achieving at least a 1-grade improvement in forehead line severity from baseline at rest, and achieving none or mild upper facial line severity at maximum contraction are also provided.

Table 2: Day 30: Investigator and Patient Assessment of Forehead Lines and Upper Facial Lines at Maximum Contraction and Rest

Clinical Study          Endpoint                  BOTOX             Placebo         BOTOX           Placebo 
Investigator Assessment              Patient Assessment
Study 191622-142        Forehead Lines at          94.8%             1.7%             87.6%           0.0% 40 U                    Max Contractiona         (184/194)          (1/60)          (170/194)        (0/60)
(20 U forehead lines                                    p < 0.0005                        p < 0.0005 + 20 U glabellar        Forehead Lines at          86.2%            22.4%             89.7%         10.2% lines)                  Restb                    (162/188)         (13/58)          (174/194)       (6/59) p < 0.0001                        p < 0.0001
Study 191622-143        Forehead Lines at          90.5%             2.7%             81.5%           3.6% 40 U                    Max Contractiona         (201/222)         (3/111)          (181/222)       (4/111)
(20 U forehead lines                                    p < 0.0005                        p < 0.0005 + 20 U glabellar        Forehead Lines at          84.1%            15.9%             83.6%         17.4% lines)                  Restb                    (185/220)        (17/107)          (184/220)      (19/109) p < 0.0001                     p < 0.0001
Study 191622-143        Forehead Lines at           93.6%              2.7%           88.9%           3.6% a
64 U                    Max Contraction           (220/235)           (3/111)       (209/235)       (4/111) (20 U forehead lines                                       p < 0.0005                     p < 0.0005 + 20 U glabellar        Upper Facial Lines          56.6%              0.9% lines + 24 U crow’s     at Max                    (133/235)           (1/111) n/a feet lines)             Contractionc                       p < 0.0001 a
Proportion of patients achieving none or mild FHL severity at maximum eyebrow elevation b
Proportion of patients with at least a 1-grade improvement from baseline of FHL severity at rest c
Proportion of responders defined as the same patient achieving none or mild in forehead lines, glabellar lines, and crow’s feet lines for each facial region at maximum contraction 
BOTOX injections significantly reduced the severity of forehead lines seen at maximum eyebrow elevation compared to placebo for up to 6 months (p < 0.05): This was measured by the proportion of patients achieving a forehead lines severity rating of none or mild at maximum eyebrow elevation in both pivotal studies; until day 150 in Study 191622-142 (21.6% with BOTOX treatment compared to 0% treated with placebo) and day 180 in Study 191622-143 (6.8% with BOTOX treatment compared to 0% treated with placebo).

When all 3 areas were treated simultaneously in Study 191622-143 (BOTOX 64 U group), BOTOX injections significantly reduced the severity of glabellar lines for up to 6 months (5.5% with BOTOX treatment compared to 0% treated with placebo), lateral canthal lines for up to 6 months (3.4% with BOTOX treatment compared to 0% treated with placebo) and forehead lines for up to 6 months (9.4% with BOTOX treatment compared to 0% treated with placebo).

A total of 116 and 150 patients received 3 cycles over 1 year of BOTOX 40 Units (20 Units forehead lines with 20 Units glabellar lines) and 64 Units (20 Units forehead lines, 20 Units glabellar lines, and 
BOT API MAR23 CL-2                                40/44
24 Units crow’s feet lines), respectively. The response rate for forehead lines improvement was similar across all treatment cycles.

Using the FLO-11 Questionnaire, improvements in patient-reported perceptions of how bothered they were by their forehead lines, looking older than their actual age, and attractiveness were observed in a significantly (p < 0.001) greater proportion of patients on BOTOX 40 Units (20 Units forehead lines with 20 Units glabellar lines) and 64 Units (20 Units forehead lines, 20 Units glabellar lines, and 24 U crow’s feet lines) compared to placebo at the primary timepoint of day 30 in Studies 191622-142 and 191622-143.

Using the Facial Lines Satisfaction Questionnaire (FLSQ), 78.1% (150/192) of patients in Study 191622-142 and 62.7% (138/220) in Study 191622-143 reported improvements in appearance-related and emotional impacts (as defined by items pertaining to feeling older, negative self-esteem, looking tired, feeling unhappy, looking angry) with BOTOX 40 Units (20 Units forehead lines with 20 Units glabellar lines) treatment compared to patients treated with placebo 19.0% (11/58) in Study 191622- 142 and 18.9% (21/111) in Study 191622-143 at day 30 (p < 0.0001 in both studies).

On the same questionnaire, 90.2% (174/193) of patients in Study 191622-142 and 79.2% (175/221, 40 Units), or 86.4% (203/235, 64 Units) in Study 191622-143 reported they were “very satisfied”/ “mostly satisfied” with BOTOX 40 Units or 64 Units compared to patients treated with placebo (1.7% [1/58], 3.6% [4/110] in Study 191622-142 and Study 191622-143, respectively), at the primary timepoint of day 60 using the FLSQ (p < 0.0001 in both studies).

In the pivotal studies, 3.7% (22/587) of patients were older than 65 years of age. Patients in this age group had a treatment response, as assessed by the investigator, of 86.7% (13/15) (at Day 30) for BOTOX compared to 28.6% (2/7) for placebo. Responder rates in this BOTOX-treated subgroup were similar to those in the overall population, but statistical significance was not reached and comparisons are difficult to make when compared to placebo due to the small number of patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

General characteristics of the active substance:
Distribution studies in rats indicate slow muscular diffusion of 125I-botulinum neurotoxin A complex in the gastrocnemius muscle after injection, followed by rapid systemic metabolism and urinary excretion. The amount of radio labelled material in the muscle declined at a half-life of approximately 10 hours. At the injection site the radioactivity was bound to large protein molecules, whereas in the plasma it was bound to small molecules, suggesting rapid systemic metabolism of the substrate.
Within 24 hours of dosing, 60% of the radioactivity was excreted in the urine. Toxin is probably metabolised by proteases and the molecular components recycled through normal metabolic pathways.
Classical absorption, distribution, biotransformation and elimination studies on the active substance have not been performed due to the nature of this product.

Characteristics in patients:
It is believed that little systemic distribution of therapeutic doses of BOTOX occurs. Clinical studies using single fibre electromyographic techniques have shown increased electrophysiologic neuromuscular activity in muscles distant to the injection site, unaccompanied by any clinical signs or symptoms.