Myobloc (Page 4 of 7)

11 DESCRIPTION

RimabotulinumtoxinB is an acetylcholine release inhibitor. RimabotulinumtoxinB is a 700 kDA botulinum toxin type B complex produced from fermentation of the bacterium Clostridium botulinum type B (Bean strain) and exists in noncovalent association with hemagglutinin and nonhemagglutinin proteins as a neurotoxin complex. The neurotoxin complex is recovered from the fermentation process and purified through a series of precipitation and chromatography steps.

MYOBLOC (rimabotulinumtoxinB) injection is a sterile, preservative-free, clear and colorless to light-yellow solution in a single-dose vial for intramuscular or intraglandular use. Each vial contains 2,500 Units/0.5 mL; 5,000 units/mL; or 10,000 Units/2 mL of rimabotulinumtoxinB at a concentration of 5,000 Units/mL at approximately pH 5.6.

Each 2,500 Units/0.5 mL vial of MYOBLOC contains 2,500 Units rimabotulinumtoxinB, 0.235 mg albumin human, 2.9 mg sodium chloride and 1.35 mg sodium succinate.

Each 5,000 Units/mL vial of MYOBLOC contains 5,000 Units rimabotulinumtoxinB, 0.47 mg albumin human, 5.8 mg sodium chloride and 2.7 mg sodium succinate.

Each 10,000 Units/2 mL vial of MYOBLOC contains 10,000 Units rimabotulinumtoxinB, 0.94 mg albumin human, 11.6 mg sodium chloride and 5.4 mg sodium succinate.

One unit of MYOBLOC corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. The method for performing the assay is specific to Solstice Neurosciences’ manufacture of MYOBLOC. Due to differences in specific details such as the vehicle, dilution scheme and laboratory protocols for various mouse LD50 assays, Units of biological activity of MYOBLOC cannot be compared to or 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 preclude extrapolation of animal dose-activity relationships to human dose estimates. The specific activity of MYOBLOC ranges between 70 to 130 Units/ng.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

MYOBLOC blocks cholinergic transmission at the neuromuscular and salivary neuroglandular junction by inhibiting the release of acetylcholine from peripheral cholinergic nerved terminals. This inhibition occurs according to the following sequence: neurotoxin binding to cholinergic nerve terminals, internalization of the neurotoxin into the nerve terminal, translocation of the light-chain part of the molecule into the cytosol of the nerve terminal, and enzymatic cleavage of synaptic Vesicle Associated Membrane Protein (VAMP, also known as synaptobrevin), a presynaptic target protein essential for the release of acetylcholine. In both muscles and glands, impulse transmission is re-established by the formation of new nerve endings.

12.2 Pharmacodynamics

In responders, the return of increased muscle tone or saliva production typically starts within 3 to 4 months after injection.

12.3 Pharmacokinetics

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No long-term carcinogenicity studies in animals have been conducted.

Mutagenesis

No genetic toxicology studies have been conducted.

Impairment of Fertility

Intramuscular administration of MYOBLOC (0, 300, 1000, or 3000 Units/kg/day) to male and female rats prior to and throughout the mating period and continuing in females to gestation day 6 resulted in decreases in implantation sites and viable fetuses at the high dose of 3000 Units/kg/day, which was associated with maternal toxicity. The no-effect dose for reproductive toxicity (1000 Units/kg/day) is 12 times the maximum recommended human dose for cervical dystonia (5000 Units) on a body weight (Units/kg) basis.

14 CLINICAL STUDIES

14.1 Cervical Dystonia

Two Phase 3, randomized, multi-center, double-blind, placebo-controlled studies of the treatment of cervical dystonia were conducted (Study 1 and Study 2). Both studies enrolled only adult patients who had a history of receiving botulinum toxin type A in an open-label manner, with a perceived good response and tolerable adverse effects. Study 1 enrolled patients who were perceived as having an acceptable response to type A toxin, while Study 2 enrolled only patients who had secondarily lost responsiveness to type A toxin. Other eligibility criteria common to both studies were that all patients had moderate or greater severity of cervical dystonia with at least 2 muscles involved, no neck contractures or other causes of decreased neck range of motion, and no history of any other neuromuscular disorder. Patients in Study 1 were randomized to receive placebo, MYOBLOC 5,000 Units or MYOBLOC 10,000 Units. Patients in Study 2 were randomized to receive placebo or 10,000 Units of MYOBLOC. The study agent was administered to subjects in a single treatment session by investigators who selected 2 to 4 muscles per subject from the following: splenius capitis, sternocleidomastoid, levator scapulae, trapezius, semispinalis capitis, and scalene muscles. The total dose was divided between the selected muscles, and from 1 to 5 injections were made per muscle. There were 109 patients enrolled into Study 1, and 77 into Study 2. Patient evaluations continued for 16 weeks post injection.

The primary efficacy outcome variable for both studies was the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total Score (scale range of possible scores is 0–87) at Week 4. TWSTRS is comprised of three sub-scales which examine 1) Severity—the severity of the patient’s abnormal head position; 2) Pain—the severity and duration of pain due to the dystonia; and 3) Disability— the effects of the abnormal head position and pain on a patient’s activities. The secondary endpoints were the Patient Global and Physician Global Assessments of change at Week 4. Both Global Assessments used a 100-point visual-analog scale (VAS). The Patient Global Assessment allows patients to indicate how they feel at the time of their evaluation compared to the pre-injection baseline. Likewise, the Physician Global Assessment indicates the physician’s assessment of a patient’s change from baseline to Week 4. Scores of 50 indicate no change, 0 much worse, and 100 much better. Results of comparisons of the primary and secondary efficacy variables are summarized in Table 4.

Table 4: Efficacy Results From Two Phase 3 MYOBLOC Studies in Cervical Dystonia
STUDY 1 STUDY 2
Assessments * Placebo (N=36) MYOBLOC 5,000 Units (N=36) MYOBLOC 10,000 Units (N=37) Placebo (N=38) MYOBLOC 10,000 Units (N=39)
*
95% Cl are for the differences between the active and placebo groups. The P values are for the comparison of active dose and placebo. For TWSTRS-Total and TWSTRS-subscale scores, P values are from ANCOVA for each variable with center and treatment in the model and the baseline value of the variable included as a covariate. For the Patient Global and Physician Global Assessments, P values are from ANOVA for each variable with center and treatment in the model.
TWSTRS Total
Mean at Baseline 43.6 46.4 46.9 51.2 52.8
Change from Baseline -4.3 -9.3 -11.7 -2.0 -11.1
95% Confidence Interval (-8.9, -1.2) (-11.1, -3.3) (-12.2, -5.2)
P value 0.012 0.0004 0.0001
Patient Global
Mean at Week Four 43.6 60.6 64.6 39.5 60.2
95% Confidence Interval (7.0, 26.9) (11.3, 31.1) (11.2, 29.1)
P value 0.001 0.0001 0.0001
Physician Global
Mean at Week Four 52.0 65.3 64.2 47.9 60.6
95% Confidence Interval (5.5, 21.3) (3.9, 19.7) (7.4, 18.1)
P value 0.001 0.004 0.0001
TWSTRS-Subscales
– Severity
Mean at Baseline 18.4 20.2 20.2 22.1 22.6
Change from Baseline -2.3 -3.2 -4.8 -1.2 -3.7
95% Confidence Interval (-2.5, 0.6) (-4.0, -1.0) (-3.9, -1.0)
P value 0.22 0.002 0.001
– Pain
Mean at Baseline 10.9 11.8 12.4 12.2 11.9
Change from Baseline -0.5 -3.6 -4.2 -0.2 -3.6
95% Confidence Interval (-4.7, -1.1) (-5.1, -1.4) (-5.0, -2.1)
P value 0.002 0.0008 0.0001
– Disability
Mean at Baseline 14.3 14.4 14.4 16.9 18.3
Change from Baseline -1.6 -2.5 -2.7 0.8 -3.8
95% Confidence Interval (-2.7, 0.7) (-2.8, 0.6) (-4.1, -1.0)
P value 0.26 0.19 0.002

There were no statistically significant differences in results between the 5,000 Unit and 10,000 Unit doses in Study 1. Exploratory analyses of these two studies suggested that the majority of patients who showed a beneficial response by Week 4 had returned to their baseline status between Weeks 12 to 16 post injection. Although there was a MYOBLOC-associated decrease in pain, there remained many patients who experienced an increase in dystonia-related neck pain irrespective of treatment group [ See Adverse Reactions, (6.1)] . TWSTRS Total Score at Week 4 and Patient Global Assessment among subgroups by gender or age showed consistent treatment-associated effects across these subgroups [see Use in Specific Populations (8.5)]. There were too few non-Caucasian patients enrolled to draw any conclusions regarding relative efficacy in racial subsets.

MYOBLOC was studied in two Phase 2 dose-ranging studies, Studies 3 and 4, which preceded the Phase 3 studies. Studies 3 and 4 had a study design similar to the Phase 3 studies, including eligibility criteria. Study 3 enrolled 85 patients randomized to placebo, MYOBLOC 400 Units, MYOBLOC 1,200 Units, or MYOBLOC 2,400 Units (21 or 22 patients per group). Study 4 enrolled 122 patients randomized to placebo, MYOBLOC 2,500 Units, MYOBLOC 5,000 Units, or MYOBLOC 10,000 Units (30 or 31 patients per group). These studies demonstrated efficacy on the TWSTRS-Total, baseline to Week 4, at doses of 2,400 Units; 2,500 Units; 5,000 Units; and 10,000 Units. Study 3 showed mean improvement from baseline on the Week 4 TWSTRS for placebo and 2,400 Units of 2.0 and 8.5 points respectively (from baselines of 42.0 and 42.4 points). Study 4 showed mean improvement from baseline to Week 4 for placebo, MYOBLOC 2,500 Units, MYOBLOC 5,000 Units, and MYOBLOC 10,000 Units of 3.3, 11.6, 12.5, and 16.4 points, respectively (from baseline of 45.5, 45.6, 45.2, and 47.5 points). Study 3 also showed less response for doses below 2,400 Units.

Study 5 was an open-label, intrapatient dose-escalation study of 3 treatment sessions where each patient with cervical dystonia sequentially received 10,000 Units; 12,500 Units; and 15,000 Units of MYOBLOC, at periods of 12 to 16 weeks between treatment sessions irrespective of their response to their previous dose. This study enrolled 145 patients, of whom 125 received all three treatments. Although this was an open-label design where investigators and patients knew the dose at each treatment session, there were similar mean improvements on the TWSTRS-Total, from baseline to Week 4, for all three doses.

In the MYOBLOC-treated patients (n=112) of the Phase 3 studies, 19% had 2 muscles injected, 48% had 3 muscles injected, and 33% had 4 muscles injected. Table 5 indicates the frequency of use for each of the permitted muscles, and the fraction of the total dose of the treatment injected into each muscle, for those patients in whom the muscle was injected.

Table 5: Study 1 and Study 2 Combined Data Fraction of Total Dose Injected into Involved Muscles in Patients with Cervical Dystonia
Muscle Injected Percent Frequency Injected * Fraction of Total Dose Injected by Percentiles
25th 50th 75th
*
Percent frequency of patients in whom each muscle was injected
Splenius Capitis 88 0.30 0.40 0.50
Sternocleidomastoid 80 0.20 0.25 0.30
Semispinalis Capitis 52 0.30 0.36 0.50
Levator Scapulae 46 0.13 0.20 0.20
Trapezius 38 0.20 0.25 0.35
Scalene Complex 13 0.20 0.25 0.30

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