Botox Cosmetic (Botulinum Toxin Type A) - Description and Clinical Pharmacology

Manufactured by: Allergan Pharmaceuticals Ireland
a subsidiary of: Allergan, Inc. 2525 Dupont Dr., Irvine, CA 92612

DESCRIPTION

BOTOX ^® Cosmetic (onabotulinumtoxinA) for injection, is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A grown in a medium containing casein hydrolysate, glucose, and yeast extract, intended for intramuscular use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying.

One Unit of BOTOX ^® Cosmetic corresponds to the calculated median intraperitoneal lethal dose (LD₅₀) in mice. The method utilized for performing the assay is specific to Allergan's product BOTOX ^® Cosmetic. Due to specific details of this assay such as the vehicle, dilution scheme and laboratory protocols for the various mouse LD₅₀ assays, Units of biological activity of BOTOX ^® Cosmetic cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. In addition, differences in species sensitivities to different botulinum neurotoxin serotypes precludes extrapolation of animal-dose activity relationships to human dose estimates. The specific activity of BOTOX ^® Cosmetic is approximately 20 Units/nanogram of neurotoxin protein complex.

Each vial of BOTOX ^® Cosmetic contains either 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride or 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

CLINICAL PHARMACOLOGY

BOTOX ^® Cosmetic blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX ^® Cosmetic produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX ^® Cosmetic.

Pharmacokinetics

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

CLINICAL STUDIES

Glabellar Lines

Two phase 3 randomized, multi-center, double-blind, placebo-controlled studies of identical design were conducted to evaluate BOTOX ^® Cosmetic for use in the temporary improvement of the appearance of moderate to severe glabellar facial lines. The studies enrolled healthy adults (ages 18 to 75) with glabellar lines of at least moderate severity at maximum frown. Patients were excluded if they had ptosis, deep dermal scarring, or an inability to substantially lessen glabellar lines even by physically spreading them apart. Subjects received a single treatment with BOTOX ^® Cosmetic (N=405, combined studies) or placebo (N=132, combined studies). Injection volume was 0.1 mL/injection site, for a dose/injection site in the active treatment groups of 4 Units. Subjects were injected intramuscularly in five sites, 1 in the procerus muscle and 2 in each corrugator supercilii muscle, for a total dose in the active treatment groups of 20 Units.

The co-primary efficacy endpoints were the investigator's rating of glabellar line severity at maximum frown and the subject's global assessment of change in appearance of glabellar lines, both at Day 30 post-injection. For the investigator rating, using a 4-point grading scale (0=none, 3=severe) a responder was defined as having a severity grade of 0 or 1. For the subject's global assessment of change, the ratings were from +4 (complete improvement) to -4 (very marked worsening). A responder was defined as having a grade of at least +2 (moderate improvement). After completion of the randomized studies, subjects were offered participation in an open label, repeat treatment study to assess the safety of repeated treatment sessions.

The combined results of these two efficacy trials are presented here. The mean age was 46 years, with 32 patients (6%) ≥ 65 years of age. Most of the subjects (82%) were women, and Caucasian (84%). At baseline, 210 patients (39%) had glabellar line severity scores at rest of moderate or severe.

In these studies, the severity of glabellar lines was reduced for up to 120 days in the BOTOX ^® Cosmetic group compared to the placebo group as measured both by investigator rating of glabellar line severity at maximum frown (Table 1), and by subject's global assessment of change in appearance of glabellar lines (Table 2).

TABLE 1. Investigator's Assessment of Glabellar Line Severity at Maximum Frown — Responder Rates (% and Number of Subjects with Severity of None or Mild)

a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, P<0.001
Day	BOTOX ® Cosmetic	Placebo	Difference a
7	74% 299/405	6% 8/132	68% (62, 74)
30b	80% 325/405	3% 4/132	77% (72, 82)
60	70% 283/403	2% 2/130	69% (64, 74)
90	48% 192/403	2% 3/128	45% (40, 51)
120	25% 102/403	2% 2/128	24% (19, 29)

TABLE 2. Subject's Assessment of Change in Appearance of Glabellar Lines — Responder Rates (% and Number of Subjects with at Least Moderate Improvement)

a 95% confidence intervals are shown in parenthesis
b Day 30: Co-Primary Efficacy Time point, P<0.001
Day	BOTOX ® Cosmetic	Placebo	Difference a
7	82% 334/405	9% 12/132	73% (68, 80)
30b	89% 362/405	7% 9/132	83% (77, 88)
60	82% 330/403	4% 5/130	78% (73, 83)
90	63% 254/403	3% 4/128	60% (54, 66)
120	39% 157/403	1% 1/128	38% (33, 43)

In the subset of patients with resting severity scores of moderate or severe, the investigator assessment of a resting severity of mild or none at day 30 was also achieved by more BOTOX ^® Cosmetic treated patients (74%, 119/161) than placebo treated patients (20%, 10/49).

Analysis of the limited number of patients 65 years or older suggested a lower treatment-associated response compared to patients less than 65 years of age. (Table 3).

TABLE 3. Investigator's and Subject's Assessment — Responder Rates for Subjects < 65 and ≥ 65 Years of Age at Day 30

a 95% confidence intervals are shown in parenthesis
Assessment	Age Group	BOTOX ® Cosmetic N=405	Placebo N=132	Difference a
Investigators (maximal frown)	< 65	83% 316/382	2% 2/123	81% (77, 86)
Subjects	< 65	91% 346/382	7% 8/123	84% (79, 90)
Investigators (maximal frown)	≥ 65	39% 9/23	22% 2/9	17% (-17, 51)
Subjects	≥ 65	70% 16/23	11% 1/9	58% (31, 86)

Exploratory analyses by gender suggested that responder rates in the BOTOX ^® Cosmetic treated group were higher for women than for men for both the investigator assessment (day 30; 85% of 334 women, 59% of 71 men) and the Subject Assessment (day 30; 93% of women, 72% of men). In the limited number of non-Caucasian patients (n=64 in the BOTOX ^® Cosmetic treated group) the responder rates were similar to those observed in the Caucasian patients.