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

DESCRIPTION

BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex 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. 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® 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®. 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® cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. Therefore, 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® is approximately 20 Units/nanogram of neurotoxin protein complex.

Each vial of BOTOX® contains 100 Units (U) of Clostridium botulinum type A neurotoxin complex, 0.5 milligrams of Albumin (Human), and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative.

CLINICAL PHARMACOLOGY

BOTOX® blocks neuromuscular transmission by binding to acceptor sites on motor or sympathetic 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® 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®.

When injected intradermally, BOTOX® produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating.

PHARMACOKINETICS

Botulinum Toxin Type A is not expected to be present in the peripheral blood at measurable levels following IM or intradermal injection at the recommended doses. The recommended quantities of neurotoxin administered at each treatment session are not expected to result in systemic, overt distant clinical effects, i.e. muscle weakness, in patients without other neuromuscular dysfunction. However, sub-clinical systemic effects have been shown by single-fiber electromyography after IM doses of botulinum toxins appropriate to produce clinically observable local muscle weakness.

CLINICAL STUDIES:

Cervical Dystonia:

A phase 3 randomized, multi-center, double blind, placebo-controlled study of the treatment of cervical dystonia was conducted. ¹ This study enrolled adult patients with cervical dystonia and a history of having received BOTOX® in an open label manner with perceived good response and tolerable side effects. Patients were excluded if they had previously received surgical or other denervation treatment for their symptoms or had a known history of neuromuscular disorder. Subjects participated in an open label enrichment period where they received their previously employed dose of BOTOX®. Only patients who were again perceived as showing a response were advanced to the randomized evaluation period. The muscles in which the blinded study agent injections were to be administered were determined on an individual patient basis.

There were 214 subjects evaluated for the open label period, of which 170 progressed into the randomized, blinded treatment period (88 in the BOTOX® group, 82 in the placebo group). Patient evaluations continued for at least 10 weeks post-injection. The primary outcome for the study was a dual endpoint, requiring evidence of both a change in the Cervical Dystonia Severity Scale (CDSS) and an increase in the percentage of patients showing any improvement on the Physicians Global Assessment Scale at 6 weeks after the injection session. The CDSS quantifies the severity of abnormal head positioning and was newly devised for this study. CDSS allots 1 point for each 5 degrees (or part thereof) of head deviation in each of the three planes of head movement (range of scores up to theoretical maximum of 54). The Physician Global Assessment Scale is a 9 category scale scoring the physician's evaluation of the patients' status compared to baseline, ranging from -4 to +4 (very marked worsening to complete improvement), with 0 indicating no change from baseline and +1 slight improvement.

Pain is also an important symptom of cervical dystonia and was evaluated by separate assessments of pain frequency and severity on scales of 0 (no pain) to 4 (constant in frequency or extremely severe in intensity). Study results on the primary endpoints and the pain-related secondary endpoints are shown in Table 1.

Exploratory analyses of this study suggested that the majority of patients who had shown a beneficial response by week 6 had returned to their baseline status by 3 months after treatment. Exploratory analyses of subsets by patient sex and age suggest that both sexes receive benefit, although female patients may receive somewhat greater amounts than male patients. There is a consistent treatment-associated effect between subsets greater than and less than age 65 (see also PRECAUTIONS: Geriatrics). There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets.

There were several randomized studies conducted prior to the phase 3 study which were supportive but not adequately designed to assess or quantitatively estimate the efficacy of BOTOX®.

In the phase 3 study the median total BOTOX® dose in patients randomized to receive BOTOX® (n=88) was 236 Units, with 25th to 75th percentile ranges of 198 to 300 Units. Of these 88 patients, most received injections to 3 or 4 muscles; 38 received injections to 3 muscles, 28 to 4 muscles, 5 to 5 muscles and 5 to 2 muscles. The dose was divided amongst the affected muscles in quantities shown in Table 2. The total dose and muscles selected were tailored to meet individual patient needs.

Primary Axillary Hyperhidrosis:

The efficacy and safety of BOTOX® for the treatment of primary axillary hyperhidrosis were evaluated in two randomized, multi-center, double-blind, placebo-controlled studies.

Study 1 included adult patients with persistent primary axillary hyperhidrosis who scored 3 or 4 on a Hyperhidrosis Disease Severity Scale (HDSS) and who produced at least 50mg of sweat in each axilla at rest over 5 minutes. HDSS is a 4-point scale with 1= "underarm sweating is never noticeable and never interferes with my daily activities"; to 4 = "underarm sweating is intolerable and always interferes with my daily activities". A total of 322 patients were randomized in a 1:1:1 ratio to treatment in both axillae with either 50 Units of BOTOX®, 75 Units of BOTOX®, or placebo. Patients were evaluated at 4-week intervals. Patients who responded to the first injection were re-injected when they reported a re-increase in HDSS score to 3 or 4 and produced at least 50mg sweat in each axilla by gravimetric measurement, but no sooner than 8 weeks after the initial injection.

Study responders were defined as patients who showed at least a 2-grade improvement from baseline value on the HDSS 4 weeks after both of the first two treatment sessions or had a sustained response after their first treatment session and did not receive re-treatment during the study. Spontaneous resting axillary sweat production was assessed by weighing a filter paper held in the axilla over a period of 5 minutes (gravimetric measurement). Sweat production responders were those patients who demonstrated a reduction in axillary sweating from baseline of at least 50% at week 4.

In the three study groups the percentage of patients with baseline HDSS score of 3 ranged from 50% to 54% and from 46 % to 50% for a score of 4. The median amount of sweat production (averaged for each axilla) was 102 mg, 123 mg, and 114 mg for the placebo, 50 Units and 75 Units groups respectively.

The percentage of responders based on at least a 2-grade decrease from baseline in HDSS or based on a >50% decrease from baseline in axillary sweat production was greater in both BOTOX® groups than in the placebo group (p < 0.001), but was not significantly different between the 2 BOTOX® doses (See Table 3).

Duration of response was calculated as the number of days between injection and the date of the first visit at which patients returned to 3 or 4 on the HDSS scale. The median duration of response following the first treatment in BOTOX® -treated patients with either dose was 201 days. Among those who received a second BOTOX® injection, the median duration of response was similar to that observed after the first treatment.

In study 2, 320 adults with bilateral axillary primary hyperhidrosis were randomized 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 measured by gravimetric measurement at 4 weeks. At week 4 post-injection, the percentages of responders were 91% (219/242) in the BOTOX® group and 36% (28/78) in the placebo group, p < 0.001. The difference in percentage of responders between BOTOX® and placebo was 55% (95% CI = 43.3, 65.9).

Blepharospasm:

Botulinum toxin has been investigated for use in patients with blepharospasm in several studies. In an open label uncontrolled study, 27 patients with essential blepharospasm were injected with 2.0 Units of BOTOX® at each of six sites on each side. One patient had not received any prior treatment. Twenty-six of the patients had not responded to therapy with benztropine mesylate, clonazepam and/or baclofen. Three of the 26 patients continued to experience spasms following muscle stripping surgery. Twenty-five of the 27 patients treated with botulinum toxin reported improvement within 48 hours. One patient was controlled with a higher dosage at 13 weeks post initial injection and one patient reported mild improvement but remained functionally impaired. ²

In another study, 12 patients with blepharospasm were evaluated in a double-blind, placebo-controlled study. Patients receiving botulinum toxin (n=8) improved compared with the placebo group (n=4). The mean dystonia score improved by 72%, the self-assessment score rating improved by 61%, and a videotape evaluation rating improved by 39%. The effects of the treatment lasted a mean of 12.5 weeks. ³

One thousand six hundred eighty-four patients with blepharospasm who were evaluated in an open label trial showed clinical improvement as evaluated by measured eyelid force and clinically observed intensity of lid spasm, lasting an average of 12.5 weeks prior to the need for re-treatment. ⁴

Strabismus:

It is postulated that when used for the treatment of strabismus, the administration of BOTOX® affects muscle pairs by inducing an atrophic lengthening of the injected muscle and a corresponding shortening of the muscle's antagonist; it was on the basis of this hypothesis that clinical studies were conducted. Six hundred seventy-seven patients with strabismus treated with one or more injections of BOTOX® were evaluated in an open label trial. Fifty-five percent of these patients improved to an alignment of 10 prism diopters or less when evaluated six months or more following injection.⁵ These results are consistent with results from additional open label trials which were conducted for this indication.⁴