Dysport - Scientific Information
|Condition:||Blepharospasm, Spasmodic Torticollis (Cervical Dystonia)|
|Form:||Intramuscular (IM), Powder|
|Ingredients:||abobotulinumtoxinA, human serum albumin, lactose monohydrate|
|Structural formula:|| |
AbobotulinumtoxinA (Botulinum toxin type A), the active ingredient in DYSPORT is a purified neurotoxin type A complex produced by fermentation of the bacterium Clostridium botulinum type A, Hall Strain. It is purified from the culture supernatant by a series of precipitation, dialysis, and chromatography steps.
AbobotulinumtoxinA is produced as a 150 kDa single polypeptide chain composed of 1296 amino acid residues (1295 after cleavage of the N-terminal methionine). After synthesis, the neurotoxin is proteolytically cleaved to generate a di-chain protein composed of a heavy chain (∼80 kDa) and light chain (∼50 kDa). On a genetic level, the toxin gene occurs in a cluster of genes which also encode for the non-toxic non-hemagglutinin protein (NTNH), a regulator protein and the hemagglutinin (HA) proteins (HA70, HA34 and HA17). These proteins and their derivatives, except for the regulator protein, form the components of the neurotoxin type A complex.
One unit of DYSPORT corresponds to the calculated median lethal intraperitoneal dose (LD50) in mice. The method for performing the assay is specific to Ipsen′s product DYSPORT. Due to differences in specific details such as vehicle, dilution scheme and laboratory protocols for various mouse LD50 assays, units of biological activity of DYSPORT are not interchangeable with units of any other botulinum toxin or any toxin assessed with any other specific assay method.
Two double-blind, randomized, placebo-controlled, Phase 3 clinical studies evaluated the efficacy of DYSPORT for use in the improvement of the appearance of moderate to severe glabellar lines. Investigator⁄Blinded Evaluators assessed efficacy by using a validated 4–point scale (none, mild, moderate, severe). Subjects assessed efficacy by using a similar static 4-point scale. These two studies enrolled ethnically-diverse, 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 (n=172) or placebo (n=117). The total dose was delivered in equally divided aliquots to specified injection sites.
Treatment success for each of the Phase 3 studies was defined as post-treatment glabellar line severity of none or mild (from moderate or severe at baseline) at maximum frown.
After completion of the randomized studies, subjects were offered participation in a three-year, open-label re-treatment study to assess the safety of multiple treatments.
Study 719 was a single dose, double-blind, multicenter, 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⁄0.05 mL (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%).
In study 719, 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 4).
A majority of DYSPORT–treated subjects (56.3%) demonstrated a 2+ grade composite (a reduction in the glabellar line severity score by a minimum of 2 grades as assessed by both the Investigator⁄Blinded Evaluator and subject) improvement, at maximum frown, at Day 30. Onset of effect was reported as soon as 24 hours; the median time to onset of treatment response was three days.
Study 085 was a repeat dose, double-blind, multicenter, placebo-controlled, randomized study to evaluate the efficacy of repeat dosing. The study was initiated with up to two open-label treatment cycles. After open-label treatment(s), subjects were randomized to receive either placebo or 50 Units of DYSPORT. Subjects receiving DYSPORT in the previous cycle, were invited to participate in the final treatment cycle, and 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.
The primary efficacy endpoint was assessed in the final treatment cycle. After the final repeat treatment with DYSPORT, the reduction of glabellar line severity at maximum frown was statistically greater at Day 30 in the DYSPORT group compared to the placebo group (p<0.001) as assessed by both Investigators and subjects (see Table 5).
A majority of DYSPORT–treated subjects (52.1%) demonstrated a 2+ grade composite improvement, at maximum frown, at Day 30. Onset of effect was reported as soon as 24 hours; the median time to onset of treatment response was three days.
The proportion of responders in the final treatment cycle was comparable to the proportion of responders in all prior treatment cycles. There was no evidence of reduced response or an increase in adverse events with repeated exposure.
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.
Studies to evaluate the carcinogenic potential of DYSPORT have not been conducted.
Genotoxicity studies have not been conducted with DYSPORT.
Fertility and Reproductive Toxicity
DYSPORT had no effect upon fertility when administered intramuscularly to rats at weekly doses up to 16 Units in females, and 10 Units in males. There were no effects upon implantation parameters at doses up to and including 8 Units. Mating was impaired at the high dose (10 Units for males and 16 Units for females), likely due to impaired hind limb function (result of the pharmacological effect on the muscle). The NOAEL for fertility and general reproduction performance was 8 Units⁄week for females and 5 Units⁄week for males.
DYSPORT was not teratogenic when evaluated in rats and rabbits. In rats, DYSPORT was administered at doses of 0.5, 1.5 and 5 Units daily from Gestation Days 6–17. Additional groups of animals received intermittent doses of 10 Units on Days 6 and 12 of gestation. There was a slight increase in fetal resorptions at the high doses of 5 Units daily and 10 Units intermittently. In rabbits, DYSPORT was administered at doses of 1, 10 and 20 Units daily from Gestation Days 6–19. Additional groups of animals received intermittent doses of 40 Units on Days 6 and 13 of gestation. All animals treated at 20 Units daily died or were sacrificed in a moribund condition, with some animals aborting. C–section data revealed comparable rates of pre–and post–implantation loss across the surviving groups. Fetal survival was not affected.
Reproductive and Developmental Effects
In a study evaluating postnatal effects, pregnant rats were given weekly doses of 1, 2.5, 5 and 10 Units from Day 6 of gestation through weaning of the litters (21 days postpartum). There was no effect of treatment on in utero survival. Evaluation of the offspring showed no effects on survival, body weights, sexual maturation, post–weaning development, mating performance or fertility. All offspring appeared normal.
Animal Toxicity Studies
DYSPORT has been evaluated in both single dose and repeated dose studies in rats. In the single dose study, DYSPORT was administered as a single intramuscular injection into the left gluteus muscle at doses of 2 or 6 Units. To evaluate reversibility of effects, subgroups of animals were sacrificed after 7, 30, 60 and 90 days of observation. No adverse systemic signs were observed, and there were no local reactions at the site of injection. Treatment related effects were limited to a reduction in the size and weight of the injected muscle, considered to be a pharmacological effect of the drug. Muscle size reduction was noted at Day 7 and Day 30 for animals treated with 6 Units and 2 Units, respectively. This was histologically confirmed as a reduction in muscle fiber size. By 90 days, muscle fiber size and resultant weights were approaching normal levels for animals treated at 2 Units, but fiber size reductions were still evident for animals treated with 6 Units. Special evaluations looking at nerves serving these muscles showed the expected disorganization early in the study, but normal nerve-muscle morphology was returning by 90 days.
In a chronic toxicity study in rats, DYSPORT was administered at 1, 4 and 12 Units given as injections at four week intervals for six injections. A fourth group of male and female animals receiving 12 U⁄adm. as 5 injections were subjected to a one month recovery period. Two control groups received the placebo on the same regimens. There was no indication of systemic toxicity at any dose and there were no signs of local irritation at the injection site. Reduced muscle size was evident at 4 and 12 Units following the first injection, but generally not evident at 1 Unit until the fifth injection. As expected there was histological evidence of atrophy of muscle fibers accompanied by minimal to moderate focal fatty infiltration and slight to minimal focal interstitial fibrosis at 1, 4 and 12 Units. Animals treated at 12 Units showed reduced body weightgain or body weight loss over the two week period following each dose with no evidence of recovery of the muscle in the rats treated at 12 Units and terminated one month after the fifth injection.
Ocular or Dermal Irritation
A local tolerance study in rabbits showed no adverse effects when instilled into the eye. There was no evidence of local effects at the site of injection in any of the above described toxicity and reproduction studies.