A new treatment for focal dystonias: incobotulinumtoxinA (Xeomin®), a botulinum neurotoxin type A free from complexing proteins
Neuropsychiatric Disease and Treatment
A new treatment for focal dystonias: incobotulinumtoxinA (Xeomin®), a botulinum neurotoxin type A free from complexing proteins
Joohi Jimenez-Shahed 0
0 Department of Neurology, Baylor College of Medicine , Houston, TX , USA
Dystonia is a movement disorder of uncertain pathogenesis that is characterized by involuntary and inappropriate muscle contractions which cause sustained abnormal postures and movements of multiple or single (focal) body regions. The most common focal dystonias are cervical dystonia (CD) and blepharospasm (BSP). The first-line recommended treatment for CD and BSP is injection with botulinum toxin (BoNT), of which two serotypes are available: BoNT type A (BoNT/A) and BoNT type B (BoNT/B). Conventional BoNT formulations include inactive complexing proteins, which may increase the risk for antigenicity, possibly leading to treatment failure. IncobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a BoNT/A agent that has been recently Food and Drug Administration-approved for the treatment of adults with CD and adults with BSP previously treated with onabotulinumtoxinA (Botox®; Allergen, Inc, Irvine, CA) - a conventional BoNT/A. IncobotulinumtoxinA is the only BoNT product that is free of complexing proteins. The necessity of complexing proteins for the effectiveness of botulinum toxin treatment has been challenged by preclinical and clinical studies with incobotulinumtoxinA. These studies have also suggested that incobotulinumtoxinA is associated with a lower risk for stimulating antibody formation than onabotulinumtoxinA. In phase 3 noninferiority trials, incobotulinumtoxinA demonstrated significant improvements in CD and BSP symptoms in both primary and secondary measures, compared with baseline, and met criteria for noninferiority versus onabotulinumtoxinA. In placebo-controlled trials, incobotulinumtoxinA also significantly improved the symptoms of CD and BSP, with robust outcomes in both primary and secondary measures. The use of incobotulinumtoxinA has been well tolerated in all trials, with an adverse event profile similar to that of onabotulinumtoxinA. Based on these data, incobotulinumtoxinA is a safe and effective BoNT/A for the treatment of CD and BSP, and may pose a lower risk for immunogenicity leading to treatment failure compared with other available BoNT agents. This paper reviews the treatment of focal dystonias with BoNTs, in particular, incobotulinumtoxinA. Controlled trials from the existing incobotulinumtoxinA literature are summarized.
network dysfunction associated with abnormalities in the
sensorimotor cortex, basal ganglia, and cerebellum.1,3–5
Dystonia is variously classified according to whether it is
primary (idiopathic) or secondary to other neurologic conditions,
injuries, abnormalities, or drug effects; childhood- or
adultonset; and the body area(s) affected.1 When described based
81 on body distribution, classifications of dystonia include: (
l-02 focal, in which one region, such as craniofacial, neck, limb,
-Ju2 or axial (shoulders, trunk), is involved, (
) segmental, which
no1 includes $2 adjacent regions, (
) multifocal, in which $2
.05 nonadjacent regions are involved, (
) generalized, which may
.351 include one or both legs, the trunk, and/or other regions, and
/.yb15 (a5ff)ehcetemdi.d1,6ysFtoocnaila,diynstwohniicahs othcecuiprsmiloatsetrfarleaqrumenstalyndinleagdsualtrse,
.com whereas generalized dystonias often begin in childhood.2
rsse Primary, adult-onset, focal dystonia is by far the most
comvpeo mon type of dystonia.1,7–9
.dww l.y The two most common types of focal dystonias, in order
/w no of prevalence, are cervical dystonia (CD; also known as
tsp sue spasmodic torticollis) and blepharospasm (BSP),7,10 although
th la BSP has been reported to be more common than CD in
lfrdedaoom rrspeoonF sdpiseocridfiecrspohpauslbaetieonnsre.1p1–o13rtTehdetoesbtiembaettewdepernevsiaxleanncde noifntehpeseer
100,000 for CD and about three per 100,000 for BSP.7,10,14
Both CD and BSP are associated with multiple adverse
effects on quality of life, including social and occupational
dysfunction and disability, embarrassment, anxiety, and
CD is characterized by involuntary contractions of cervical
muscles that cause abnormal head movements and postures,
and may feature jerking or twisting movements, transient
spasms, shoulder elevation, stiffness/tightness, and an
irregular jerky head tremor.15,20 Individuals with BSP, on the other
hand, exhibit involuntary, repetitive, spasmodic, and sustained
eyelid closure.21,22 A hallmark of both BSP and CD, as well as
other forms of dystonia, is the presence of a sensory trick, or
“geste antagoniste,” that may assist a patient in maintaining
a normal posture.23 Mean age at onset is about 41 years for
persons with CD and 56 years for those with BSP.24 Despite
these differences in clinical features, CD and BSP may share
etiologic and pathophysiologic mechanisms.25 In patients with
CD, BSP occurs concomitantly in approximately 10% of those
affected,20,26 and about 30% of patients with BSP experience
spread of dystonic symptoms to the neck.27 Both CD and BSP
appear to be associated with a bilateral reduction in striatal
postsynaptic dopamine D2 receptor binding, as indicated
by functional imaging studies,28–30 although recent findings
suggest that the defect in focal dystonia may be in D3, rather
than D2, receptor expression.31 In addition, both CD and BSP
have been associated with enhancement of the blink reflex,
which suggests hyperexcitability of brainstem pathways,32–34
impaired recognition of facial expression of disgust, which
involves basal ganglia activation,35 and bilateral impaired
sensory spatial discrimination, which suggests abnormal
sensory processing within the somatosensory cortex.36
A brain voxel-based morphometry study also revealed similar
alterations in gray matter structures related to sensorimotor
processing in patients with BSP and CD.37
The aim of this review is to familiarize the clinician with
the differing biological and physical properties of botulinum
toxins (BoNTs) used for treatment of focal dystonias and
to summarize the clinical profile of incobotulinumtoxinA
(Xeomin®; Merz Pharmaceuticals GmbH, Frankfurt,
Germany), the most recently Food and Drug Administration
The clinical data for incobotulinumtoxinA summarized in this
review were obtained by performing a PubMed search using
the terms “Xeomin,” “NT201,” “NT 201,” and
“incobotulinumtoxinA.” Two phase 1 trials in healthy volunteers were
identified in the search and were included in the review. All
clinical trials in focal dystonia (CD or BSP) identified via
this search were also included; additionally, pooled analyses
and subanalyses generated from these trials and presented
at society conferences were included. All the clinical trials
in focal dystonia were well-controlled, double-blind trials
with the exception of an open-label immunogenicity trial in
CD that reported an objective outcome measure: presence
of neutralizing antibodies.
BoNT treatment of focal dystonia: overview
BoNT is the first-line recommended treatment for most types
of focal dystonia, including both CD and BSP.38,39 BoNT
acts primarily by binding with high specificity and
affinity to presynaptic cholinergic axon terminals and blocking
the release of acetylcholine into the neuromuscular
junction, thereby causing temporary denervation and muscle
weakness for periods typically lasting 3–4 months.40,41 A total
of seven antigenically distinct serotypes (types A–G) of
naturally occurring toxin have been isolated from unique
strains of Clostridium botulinum. These serotypes vary by
their mechanism of blocking fusion of the
acetylcholinecontaining synaptic vesicle with the cell membrane, thereby
preventing neurotransmitter release into the neuromuscular
BTX–B, D, F, G, TeTx
BTX–A, E, C1
Steps: 1 2 Plasma membrane 3
junction and achieving denervation (Figure 1).40,41 BoNT
type A (BoNT/A) cleaves the target protein
synaptosomalassociated protein 25 and BoNT type B (BoNT/B) cleaves
synaptobrevin-2 (Figure 1); these serotypes are used in
The most commonly used BoNT treatments include three
BoNT/A products and one BoNT/B product, each of which
has a unique generic name designated by the FDA for use
in the United States (Table 1).42,43 All of these agents have
demonstrated efficacy in clinical trials, but they have
varying pharmacologic properties including potency, dosing,
constituents and excipients, storage requirements, and
tolerability profiles (Table 1).38,39,41,44–46 However, only a modest
number of randomized, controlled clinical trials comparing
BoNT agents in patients with focal dystonia have been
reported in the literature.44,45,47–51
Currently-marketed BoNT agents may vary with respect
to their risk for stimulating antibody formation,
leading to immunoresistance and the potential for treatment
failure.41,52,53 In patients being treated for CD, de novo
treatment with BoNT/B has been associated with a high rate of
immunoresistance, contributing to treatment failure in up to
44% of individuals.54 The rate of immunoresistance in type A
agents appears to range from ,1% to 5%.2,53,55 Possible risk
factors for immunoresistance include higher doses, the total
amount of clostridial protein administered, and increased
duration and frequency of treatment.52,53 Clinical data also
suggest that patients may vary in their immune reactivity to
similar doses of BoNT.53 The issue of immunoresistance is
of particular importance in patients with dystonia, because
limited options are available for the management of BoNT/A
failure. For example, a study of ten patients with CD who
had experienced complete therapeutic failure with BoNT/A
found that alternative BoNT/B treatment induced a stable
therapeutic response in three of the participants, but only
a temporary response followed by treatment failure in the
remainder of the individuals.56
The presence of nontoxic hemagglutinizing and
nonhemagglutinizing complexing proteins in several of the
available BoNT agents (Table 1) may also lead to
immunoresistance.53,57 The neurotoxin present in all serotypes of BoNT
(types A–G) is noncovalently associated with complexing
submit your manuscript | www.dovepress.com
proteins to form toxin complexes, which are encoded in
two gene clusters57 and are present in the natural state. The
first cluster encodes the actual neurotoxin and a nontoxic,
nonhemagglutinin protein, and the second cluster encodes
three hemagglutinin proteins (HA1, HA2, and HA3).58,59 Two
different complexes are produced by C. botulinum (serotypes
18 A–D and G): a complex containing the toxin and the nontoxic,
l-02 nonhemagglutinin protein (300 kDa), and a larger complex
-Ju2 containing the toxin and HA1–3 (500–600 kDa). Serotype
n1o A also forms a third complex with an even higher molecular
.05 weight. This complex contains the toxin and nontoxic,
nonhe.153 magglutinin protein in addition to varying numbers of other
.y15 hemagglutinin proteins (880–1000 kDa in total).57 Based on
/b experimental studies, the natural functions of the complexing
.com proteins appear to include protecting the neurotoxin from low
rsse pH and proteases, stabilizing the neurotoxin’s biologic
activvpeo ity, and facilitating adherence of the neurotoxin to muscle
.ww l.y tissues,57,60–62 suggesting a role in preventing degradation
/w no of the toxin within the gastrointestinal tract and
tsp sue ing the likelihood of absorption – hence, a biologic effect.
th la Hypothetically, by increasing the size (molecular weight) of
lfrdedaoom rrspeoonF tfhuesitoonxionf cthoemnpeleuxro,tcooxminpoleuxtinogf
tphreotteairngsetmtiasysuael,sopolitmenittiadlilfylowering the risk for such diffusion-related adverse events
(AEs) as dysphagia in patients with CD.62,63 Experimental
studies suggest, however, that BoNT complexing proteins
are not essential for the clinical activity of the neurotoxin
in humans, because at increasing pH levels, the complexes
quickly dissociate at an increasing rate.64 At physiologic pH
in humans, this process occurs in ,1 minute,65 whereas the
clinical effect is known to become augmented over days.
Experimental and clinical studies have also shown that
complexing proteins do not appear to modify the diffusion
of BoNT from target tissues.64–68
In addition, assay studies have found that complexing
proteins have significantly greater immunogenicity than does
the purified neurotoxin alone, with antibody formation up
to 60 times greater in reaction to the BoNT complex and
up to 35 times greater in reaction to the complexing
hemagglutinins, compared with the neurotoxin alone.69–71 Although
the precise relationship between antibody formation and
treatment failure is unclear, almost half of all secondary
nonresponders to BoNT therapy for focal dystonia screen
positive for antibody formation.72 It has been speculated
that the immune activity generated by the presence of
complexing proteins can induce a greater likelihood of an
antigenic response against the neurotoxin itself – that is, a
Review of incobotulinumtoxinA
History of development
IncobotulinumtoxinA (Xeomin) is a highly purified BoNT/A
agent and the only BoNT product that is free of any complexing
clostridial proteins (Table 1).65 IncobotulinumtoxinA is
FDA-approved for the treatment of adults with CD in both
BoNT-naïve individuals and previously-treated patients, and
for the treatment of BSP in adults previously treated with
onabotulinumtoxinA (Botox®; Allergen, Inc, Irvine, CA).73
Prior to the development of incobotulinumtoxinA, the
manufacturing process of BoNT agents was hampered by a
massive degradation of about 90% of the neurotoxin, with this
proportion inactive and behaving as a toxoid.65 A high level of
inactive clostridial protein in a BoNT formulation is clinically
important, because it increases the total amount of clostridial
protein that must be administered to achieve a therapeutic
effect, which, as noted, may increase the risk for an immune
reaction.65,74 In addition, both the diffusion of BoNT and the
incidence of BoNT-related AEs have been observed to be
In view of these factors, a manufacturing process for
incobotulinumtoxinA was devised that involves a series of
steps to separate and purify the neurotoxin complex, eliminate
the complexing proteins, minimize degradation, and prevent
loss of biologic activity during dilution, formulation, and
lyophilization.65 As a result, incobotulinumtoxinA contains
only the pure 150 kDa neurotoxin and contains 0.6 ng of
protein per every 100 U vial.65 By contrast, there is about
55 ng of protein in a vial of rimabotulinumtoxinB (Myobloc®/
Neurobloc®; Solstice Neurosciences, Malvern, PA), 5 ng in a
vial of onabotulinumtoxinA, and 4.35 ng in a vial of
abobotulinumtoxinA (Dysport®; Ipsen, Paris, France).65,66 Complexing
proteins add to the molecular weight of the injected solution
and may hypothetically enhance the stability of the product
and limit its diffusion to adjacent tissues. Given that
incobotulinumtoxinA lacks the complexing proteins of other BoNT
agents, it was evaluated for these pharmacologic properties,
as well as for safety, tolerability, and efficacy.
Stability studies conducted in accordance with the FDA
guidelines for stability testing of drug products78 revealed
that incobotulinumtoxinA remained stable and highly potent
when stored for 4 years at room temperature, thereby
demonstrating that complexing proteins are not necessary for
stabilization of a BoNT formulation prior to injection.79 To address
concerns about the greater risk for toxin spread, a randomized,
controlled, double-blind, 52-week trial in 32 male volunteers68
was conducted to study diffusion into adjacent muscles of
incobotulinumtoxinA compared with the higher molecular
weight onabotulinumtoxinA. All subjects were injected with
one agent in the extensor digitorum brevis (EDB) muscle of
one foot and the other agent in the EDB of the contralateral
foot, in equal doses (2, 4, 16, or 32 U). Surface
electromyography was used to measure whether the amplitude of the
compound muscle action potential (CMAP) in the adjacent
muscles had been reduced with either neurotoxin. The study
found that all incobotulinumtoxinA and onabotulinumtoxinA
doses significantly reduced the CMAP M-wave amplitudes
in the target EDB muscles in a dose-dependent fashion,
with similar reductions in CMAP M-wave amplitudes in
muscles adjacent to the EDB (abductor digiti quinti and
abductor hallucis).68 In fact, the CMAP M-wave amplitudes
remained above the predefined threshold of effect, indicating
that no clinically relevant diffusion had occurred. Hence, the
absence of complexing proteins in BoNT formulations does
not appear to increase the risk for diffusion of toxin.
Preclinical animal studies were also conducted to
evaluate the immunogenicity of incobotulinumtoxinA. In
a comparison study, female New Zealand white rabbits
(n = 20 per group) received intracutaneous administration
of either incobotulinumtoxinA or onabotulinumtoxinA at
16 lethal dose units per animal (approximately 5.34 lethal
dose units/kg) for eight administrations at 2- to 8-week
intervals, with a booster injection of 25 lethal dose units
per animal at 10 weeks following the eighth injection.80
Sera from both groups were initially screened for BoNT/A
antibodies using an enzyme-linked immunosorbent assay,
and antibody-positive sera were then tested for their ability
to neutralize the paralytic effects of BoNT/A in a mouse
hemidiaphragm assay. At week 36 – 3 weeks after the final
(booster) injection – the enzyme-linked immunosorbent
assay showed that seven of the 20 rabbits in the
onabotulinumtoxinA group screened positive for BoNT/A antibodies,
with four of these rabbits displaying BoNT/A-neutralizing
activity in the hemidiaphragm assay. In contrast, one rabbit
in the incobotulinumtoxinA group tested positive by
enzymelinked immunosorbent assay, but no neutralizing activity
was detected in the hemidiaphragm assay. Considering the
high doses and short injection intervals used in this study,
these results suggest that incobotulinumtoxinA, without
complexing proteins, poses a lower risk for
immunogenicity leading to treatment failure than does the conventionally
prepared BoNT/A agent that contains such proteins.80
Other preclinical animal studies have demonstrated a
similar pharmacologic profile of incobotulinumtoxinA and
onabotulinumtoxinA with respect to pharmacodynamic
action, effects on cardiovascular function and toxicity
following single or repeated dose administrations.80
In addition, two phase 1 clinical studies in healthy volunteers
showed that treatment with either incobotulinumtoxinA or
onabotulinumtoxinA was associated with similar times to onset
and duration of effect, as measured by surface
electromyography of the injected EDB muscle.68,81 The degree of reduction in
CMAP amplitudes at 3 months following the injection is
identical between the two toxin products.81 Taken together, these
studies indicate that the clinical effects of a BoNT/A product
free of complexing proteins should be no different from those
of a conventionally prepared BoNT/A formulation.
Efficacy in patients with CD
The efficacy, safety, and tolerability of incobotulinumtoxinA
have been evaluated in multiple clinical trials in patients
with CD. The largest trial to date was a randomized,
activecontrolled, double-blind, phase 3 study designed to determine
whether incobotulinumtoxinA was noninferior in efficacy to
onabotulinumtoxinA in patients with CD.51 The study, which
was conducted at 51 centers in eleven European countries,51
enrolled 463 patients with a documented stable therapeutic
response to onabotulinumtoxinA over the prior two
injection sessions, with the last onabotulinumtoxinA injection
administered at least 10 weeks prior to randomization.51,82
The patients were randomized to either incobotulinumtoxinA
or onabotulinumtoxinA at the same doses they had received
in the previous two prerandomization sessions with
onabotulinumtoxinA. The dosage ranged from 70 U to 300 U,
with a control visit conducted 4 weeks after injection and
follow-up visits for up to 16 weeks. The primary efficacy
variable was the change from baseline in the Toronto Western
Spasmodic Torticollis Rating Scale (TWSTRS)83 severity
) at 28 ± 7 days postinjection. At baseline, patients
in both the incobotulinumtoxinA group (n = 209) and the
onabotulinumtoxinA group (n = 205) had a median TWSTRS
severity score of 18, indicating moderate severity.
In both groups, these scores improved to a median of
eleven points at day 28, with an average change of −6.6 points
in the incobotulinumtoxinA group and −6.4 points in the
onabotulinumtoxinA group (P , 0.0001, analysis of
covariance, both agents; Figure 2). The median dose injected
was 120 U in the incobotulinumtoxinA group and 122.5 U
in the onabotulinumtoxinA group. In the noninferiority
assessment, the least-squares mean difference between the
groups was −0.33 points (favoring incobotulinumtoxinA)
and the upper limit of the corresponding 95% confidence
.y5 IncobotulinumtoxinA OnabotulinumtoxinA
/w no interval was lower than the predefined difference of 1.3
tsp sue points in all analysis of covariance models, thereby
demthom lsaon onstrating the noninferiority of incobotulinumtoxinA to
ldedao rpeoF onnoarbeoletuvlainntu mditfofexriennAcefosritnheantryeastemcoenndtaorfyCvDa.rIianbaldesdiwtioerne,
reported between the two groups, including the TWSTRS
severity score at the final visit, the TWSTRS pain subscore
at the control and final visits, and the visual analog scale
pain score at the control and final visits (Table 2). Both
treatments were also very similar in terms of time to onset
of effect, time to waning of effect, and total duration of
effect (Table 2). AEs were reported by similar percentages
of patients in the incobotulinumtoxinA (28.1%) and
onabotulinumtoxinA (24.1%) groups (Table 3), and serious
AEs (SAEs) occurred in four incobotulinumtoxinA-treated
patients and five onabotulinumtoxinA-treated patients.51
All SAEs were judged either unrelated or unlikely to
be related to treatment.51 The results of this study
suggest that incobotulinumtoxinA, when administered at
the same doses as prior successful onabotulinumtoxinA
treatments, is noninferior in clinical efficacy to
onabotulinumtoxinA for the treatment of CD and has a similar
side effect profile.
Another study investigated the safety and efficacy of
incobotulinumtoxinA versus placebo in 233 patients with
CD, including BoNT-naïve patients (39% of the population)
and nonnaïve individuals (previously treated with BoNT/A
or BoNT/B), at a low (120 U) and high (240 U) dose.84 The
dosing design of this study was based on the median dose
used in the noninferiority trial of incobotulinumtoxinA
and onabotulinumtoxinA (120 U),51 and the typical dose
used in other trials of BoNT/A agents for the treatment
of CD (240 U).85 This randomized, placebo-controlled
trial, conducted at 37 study centers in the United States,
submit your manuscript | www.dovepress.com
TwSTRS severity score
at final visit
TwSTRS pain subscore
at control visit
TwSTRS pain subscore
at final visit
vAS pain score
at control visit
vAS pain score
at final visit
Time to event, mean (SD)
(n = 209)
(n = 213)
(n = 210)
(n = 210)
(n = 207)
found that the changes from baseline to week four in
total TWSTRS score were −9.9 ± 10.4 points with
incobotulinumtoxinA 120 U and −10.9 ± 11.7 points with
incobotulinumtoxinA 240 U, compared with −2.2 ± 7.3
points with placebo (P , 0.001 versus placebo for both
incobotulinumtoxinA groups) (Figure 3). AEs occurred
in 55.1% of patients in the incobotulinumtoxinA 120-U
group, 56.8% in the incobotulinumtoxinA 240-U group, and
45.9% in the placebo group. The most frequently reported
AEs – dysphagia, neck pain, and muscular weakness – were
similar to those observed in the other incobotulinumtoxinA
Subanalyses of the data from this placebo-controlled trial
were also conducted in the subgroups of BoNT-naïve and
nonnaïve patients. In the toxin-naïve patients (n = 90), the
changes from baseline to week four in total TWSTRS score
with incobotulinumtoxinA 120 U and incobotulinumtoxinA
240 U were −11.9 ± 11.1 points and −10.0 ± 9.2 points,
respectively, versus −2.0 ± 6.0 with placebo (P , 0.001
for both doses).86 Changes in the TWSTRS severity score
from baseline to week four in the incobotulinumtoxinA
120-U group and the incobotulinumtoxinA 240-U group
were −4.1 ± 4.3 points and −5.4 ± 5.5 points, respectively,
versus −1.9 ± 4.5 points in the placebo group. Compared
with placebo, incobotulinumtoxinA was well tolerated,
with dysphagia, muscular weakness, and neck pain the
most frequently reported AEs with active treatment, which
is similar to that with other toxins. The subanalysis in the
patients previously treated with another BoNT product
(n = 143) showed that the mean changes in total TWSTRS
score from baseline to week four with incobotulinumtoxinA
120 U and incobotulinumtoxinA 240 U were −8.5 ± 9.7
points and −11.4 ± 13.1 points, respectively, compared
with −2.4 ± 9.1 points with placebo (P , 0.002 for both
doses).87 The improvements in TWSTRS severity score from
baseline to week four with incobotulinumtoxinA 120 U and
incobotulinumtoxinA 240 U were −3.7 ± 4.4 points and
−5.6 ± 6.4 points, respectively, versus −1.9 ± 3.7 points with
placebo. AEs occurred in 55.3% of patients in the
incobotulinumtoxinA 120-U group, 46.0% in the
incobotulinumtoxinA 240-U group, and 34.8% in the placebo group.
The most common AEs were dysphagia, neck pain, and
injection-site pain, which was similar to those reported in
the trial of BoNT-naïve patients.86
Taken together, the placebo-controlled study in patients with
CD and subanalyses of the data showed that
incobotulinumtoxinA generally has similar efficacy and tolerability at doses of
120 U and 240 U, and across BoNT-naïve and nonnaïve
Long-term safety and tolerability in patients with CD
The first long-term safety and tolerability evaluation of
incobotulinumtoxinA88 was conducted as an extension of
the above-described efficacy study in 233 patients with
CD, including both BoNT-naïve patients and those who
had been previously treated with BoNT (type A or B).84
Patients who completed the #20-week randomized,
placebo-controlled study were eligible to enter the
extension phase and were treated with incobotulinumtoxinA
(120 U or 240 U; #5 injections) over 1 year (48-week
treatment and 20-week follow-up). A total of 217 patients
entered the extension phase, with 153 of them
participating in the long-term safety analysis. The mean duration of
time prior to reinjection was 10.0–14.5 weeks. During the
extension period, 118 of the 153 patients (77.1%)
experienced at least one AE (70.7% in the 120-U group; 83.3%
in the 240-U group). The most frequently reported AEs
were dysphagia, neck pain, and sinusitis. No SAEs were
judged to be related to the incobotulinumtoxinA treatment,
and the total incidence of AEs decreased with each
injection interval, thus indicating no cumulative effect from
ldedaoom rspeoonF tarnedat1m:4enftoartaabdoobsoetruelliantuiomntsohxipinoAf.1P:1atfioernotsnapbreovt uioliunsulmyttroexaitneAd
with rimabotulinumtoxinB had been switched from either
onabotulinumtoxinA or abobotulinumtoxinA because of
nonresponse related to immunoresistance. Antibody testing
performed after 1 year and 2 years of continuous treatment
with incobotulinumtoxinA demonstrated that no patient had
developed secondary nonresponsiveness or antiBoNT/A
neutralizing antibodies, including 100 patients who had
been treated for .1 year and 34 patients who were treated
continuously for .2 years. However, six patients who had
experienced secondary nonresponsiveness as a result of
antibody formation during their prior treatment with
onabotulinumtoxinA or abobotulinumtoxinA also failed to achieve
clinical benefit with incobotulinumtoxinA, underscoring the
importance of minimizing the risk for immunoresistance from
Efficacy in patients with BSP
A phase 3 randomized, active-controlled,
doubleblind, noninferiority study comparing the eff icacy of
incobotulinumtoxinA with that of onabotulinumtoxinA
in patients with BSP was conducted at 42 study centers
in Europe and Israel.89 In this trial, 300 patients with
BSP who had received at least two prior injections with
onabotulinumtoxinA that yielded a stable response were
randomized to either incobotulinumtoxinA (n = 148) or
submit your manuscript | www.dovepress.com
Neuropsychiatric Disease and Treatment 2012:8
onabotulinumtoxinA (n = 152), with a maximum dose of
35 U per eye, and followed for 16 weeks with a control
visit at 3 weeks. The primary efficacy variable was change
from baseline in the sum score of the Jankovic Rating Scale
(JRS) at the control visit (21 ± 1 days postinjection).89
Each of the treatments resulted in similar reductions in
JRS scores of −2.90 in the incobotulinumtoxinA group
and −2.67 in the onabotulinumtoxinA group, both of which
were significant compared with baseline (P , 0.0001,
analysis of covariance, for both; Figure 4). The difference
between the two adjusted group means was −0.23, with
the upper limit of the 95% confidence interval
amounting to 0.22.89 This was below the predefined limit for
noninferiority (0.8), thus demonstrating that
incobotulinumtoxinA was noninferior to onabotulinumtoxinA for
the treatment of patients with BSP. The noninferiority of
incobotulinumtoxinA to onabotulinumtoxinA was also
supported by the results for secondary variables, including
mean change from baseline at the control visit in scores on
the Blepharospasm Disability Index (BSDI),17 the Patient
Evaluation of Global Response,90 and the Global
Assessment Scale.91 Both agents significantly reduced mean
BSDI scores and Patient Evaluation of Global Response
scores from baseline to the control visit and the final
visit (P , 0.0001 for all changes), with no significant
differences between incobotulinumtoxinA and
onabotulinumtoxinA observed. For the Global Assessment Scale
measure, investigators rated the efficacy of the medication
as “very good” in a slightly higher percentage of patients
in the incobotulinumtoxinA group (34.9%) than in the
onabotulinumtoxinA group (28.4%); however, this
difference was not significant.89
Both study medications were well tolerated, with
slightly fewer total AEs reported in the
incobotulinumtoxinA group (56 events) than in the onabotulinumtoxinA
group (62 events). The most commonly occurring AE with
both agents was eyelid ptosis, which was reported in 6.1%
of incobotulinumtoxinA-treated patients versus 4.6% of
onabotulinumtoxinA-treated individuals (Table 4).89
IncobotulinumtoxinA was also compared with
onabotulinumtoxinA in a smaller randomized, double-blind,
parallelgroup, pilot trial.92 Patients with BSP previously treated with
onabotulinumtoxinA ($20 U per eye) and scores .2 on the
JRS (n = 65) received 20–45 U per eye of
incobotulinumtoxinA (n = 33) or onabotulinumtoxinA (n = 31) during a
single treatment session. Patients were evaluated at 4, 8, and
14 weeks postinjection. The primary outcome variable was
change in BSDI at week four. BSDI decreased from baseline
in both groups at week four (1.3 for incobotulinumtoxinA
and 2.8 for onabotulinumtoxinA) and at week eight (0.8 for
incobotulinumtoxinA and 1.3 for onabotulinumtoxinA).
JRS score decreased by 1.5 (both eyes) at week four and
1.3 (both eyes) at week eight for incobotulinumtoxinA.
JRS score decreased by 2.3 (OS) and 2.2 (OD) at week
four and 1.9 (both eyes) at week eight with
onabotulinumtoxinA treatment. There were no significant differences
between BoNT/A products in these outcome variables or
any predefined outcomes. AE profiles were similar with
periorbital hematoma reported most frequently (27% for
incobotulinumtoxinA and 23% for onabotulinumtoxinA),
followed by headache (21% for incobotulinumtoxinA and
23% for onabotulinumtoxinA).92
The safety and efficacy of incobotulinumtoxinA versus
placebo was further evaluated in a larger, randomized,
double-blind study in patients with BSP with documented
satisfactory response to two previous treatments with
onabotulinumtoxinA and JRS severity subscores $2.93
A total of 109 patients were randomized in a 2:1 ratio to
an individual dose of incobotulinumtoxinA, at up to 50 U
per eye, or placebo, and were followed for up to 20 weeks.
The primary efficacy measure was change from baseline
at 6 weeks postinjection in the JRS severity subscore, as
assessed by a blinded independent investigator. At 6 weeks,
the JRS severity subscore had improved signif icantly
more in the incobotulinumtoxinA group, by −0.83 points,
compared with a 0.21 increase (worsening) with placebo,
resulting in a difference of 1.0 favoring
incobotulinumtoxinA (P , 0.001).93 Functional impairment as indicated
by BSDI scores improved by 0.5 points with
incobotulinumtoxinA compared with placebo (P = 0.002). AEs were
reported in 70.3% of patients in the incobotulinumtoxinA
group and 58.8% in the placebo group. The most
commonly reported AEs (incobotulinumtoxinA versus placebo)
were eyelid ptosis (18.9% versus 5.9%), dry eye (18.9%
versus 11.8%), and dry mouth (14.9% versus 2.9%).
Tolerability was rated as good/very good by 91.9% patients in
the incobotulinumtoxinA group compared with 85.2% of
Pooled data analyses
Pooled analyses of data from multiple clinical trials were
conducted to evaluate the overall efficacy, safety, and tolerability
of incobotulinumtoxinA across both CD and BSP patient
populations. In one such analysis, efficacy data were pooled
from two pivotal clinical trials in patients with CD and BSP,51,89
which included a total of 343 incobotulinumtoxinA-treated
patients and 340 onabotulinumtoxinA-treated patients, as
well as one trial for the treatment of spasticity in poststroke
patients, which included 73 incobotulinumtoxinA-treated
patients and 75 placebo-treated individuals.94 For the
evaluation of safety and tolerability, this analysis also pooled data
from six clinical trials in patients with BSP, CD, and upper
limb spasticity, including 539 incobotulinumtoxinA-treated
patients, 442 onabotulinumtoxinA-treated patients, and 75
placebo-treated patients. The results of this analysis showed
that incobotulinumtoxinA and onabotulinumtoxinA have
equivalent efficacy, with similar onset, waning, and duration
of effect. These results were confirmed by similar ratings for
both agents in the physician Global Impression of Efficacy,
in which 70.6% of onabotulinumtoxinA-treated patients and
71.8% of incobotulinumtoxinA-treated patients were rated
81 as “good” or “very good.” No clinically relevant differences
l-20 were detected between active treatment groups in the focal
-Ju2 dystonia trials, or between incobotulinumtoxinA and placebo
no1 in the poststroke spasticity trials. All AEs were either already
.50 known and/or were judged by the investigator as unlikely to
.531 be related to incobotulinumtoxinA treatment. This analysis
.y51 further estimated that as of 2009, .67,000 patients had
/b been treated with incobotulinumtoxinA, with no new safety
.com concerns having been reported.95
rsse Another pooled analysis was conducted to evaluate
vpeo the eff icacy of incobotulinumtoxinA in CD and BSP
.dww l.y populations.95 This analysis included two active-controlled
/w no trials51,89 and two placebo-controlled trials,84,93 one each in the
tsp sue CD and BSP populations. Efficacy data were available for a
thom lsaon total of 613 patients who had received incobotulinumtoxinA
ldedao rpeoF treatment. In the placebo-controlled studies, the mean
age improvement with incobotulinumtoxinA versus placebo
nw in the primary efficacy outcomes was similar across studies
tod (23.2%–26.5%), and patient-evaluated global response to
tenm treatment was significantly superior compared with placebo
rea (P , 0.001); 53.4% of incobotulinumtoxinA-treated patients
dnT reported at least moderate symptomatic improvement
comsea pared with 12.0% of placebo-treated individuals. Across the
isea four studies, the mean onset of treatment was 6.0–7.7 days,
iitrchaD dthueramtieoannowfaenfifnegctowfeafsfe1c0t.6w–a1s46.0.5–w1e0e.k6sw.95eeks, and the mean
csyp In addition, a review of the AEs in the two noninferiority
reuo trials of incobotulinumtoxinA and onabotulinumtoxinA showed
N that most AEs associated with the use of either agent were of
mild or moderate severity (Table 5).80 The incidence of SAEs
was also low across both studies, occurring at a slightly lower
rate with incobotulinumtoxinA than with onabotulinumtoxinA;
no deaths were reported during these trials (Table 5).80 None of
the SAEs was considered to be related to the study medication in
either trial; no AEs led to treatment withdrawal in the
incobotulinumtoxinA groups, whereas only one withdrawal due to an AE
was reported with the use of onabotulinumtoxinA (Table 5).80
Review of the data
Overall, a considerable amount of preclinical and clinical trial
data on incobotulinumtoxinA has been collected, including
individual studies and pooled analyses of these studies. The
submit your manuscript | www.dovepress.com
preclinical data established that incobotulinumtoxinA will
remain stable for up to 4 years at room temperature79 and
demonstrated a low risk for diffusion from target tissues
following injection, which is similar to that with
onabotulinumtoxinA.68 In addition, preclinical data demonstrated that
incobotulinumtoxinA has a low potential for immunogenicity
leading to treatment failure, which was lower than that with
onabotulinumtoxinA.80 In an ongoing clinical trial in patients
with CD, no cases of antibody formation were reported in 100
patients who had been treated for .1 year and in 34 patients
treated continuously for .2 years.94 In clinical studies in
healthy volunteers, incobotulinumtoxinA also demonstrated a
similar pharmacologic profile to onabotulinumtoxinA in terms
of onset of effect, duration of effect, and overall efficacy,51,81
as well as pharmacodynamic actions and adverse effects.80
Randomized, active-controlled, clinical studies have
shown that incobotulinumtoxinA is noninferior in efficacy to
onabotulinumtoxinA for the treatment of both CD and BSP.51,89
A randomized, controlled study also determined that
incobotulinumtoxinA significantly reduced CD symptoms compared
with placebo in BoNT-naïve and nonnaïve patients.84,86,87
In patients with BSP who had been previously treated with
BoNT, incobotulinumtoxinA signif icantly reduced BSP
symptoms compared with placebo.93 Across the clinical CD
trials, both the primary efficacy measures (which were either
the TWSTRS total score or the TWSTRS severity score in all
trials) and the secondary outcomes (including both
patientand physician-rated scales) demonstrated the noninferiority of
incobotulinumtoxinA to onabotulinumtoxinA and significant
benefits, compared with placebo. In patients with BSP
previously treated with BoNT, secondary measures, including the
BSDI, Patient Evaluation of Global Response, and Global
Assessment Scale, also supported the primary outcome result
(JRS total score) in demonstrating the noninferiority of
incobotulinumtoxinA to onabotulinumtoxinA and the superiority
of incobotulinumtoxinA compared with placebo.17,89,93
With regard to safety and tolerability,
incobotulinumtoxinA is well tolerated, and has demonstrated an AE profile
similar to that of onabotulinumtoxinA in both CD and BSP
patients (Tables 3 and 4).51,89 Most AEs associated with
either agent are of mild to moderate severity, and few have
led to withdrawal from treatment (Table 5).80 It also should
be noted that incobotulinumtoxinA is contraindicated in
people with known hypersensitivity to BoNT/A or to any
of the excipients used in this product (Table 1), or with
generalized disorders of muscle activity (eg, myasthenia
gravis, Lambert–Eaton syndrome).73,80 Patients treated with
incobotulinumtoxinA should be closely observed when
Neuropsychiatric Disease and Treatment 2012:8
Measure, n (%)
Cervical dystonia trial
(n = 463)
(n = 231)
Total number of patients with AEs
Patients with SAEs
Total number of SAEs
AEs leading to withdrawal
AEs leading to death
there is concomitant use of agents that may potentiate the
effects of incobotulinumtoxinA, including aminoglycoside
antibiotics, spectinomycin, or other agents that interfere with
neuromuscular transmission (eg, tubocurarine-like agents),
or muscle relaxants.73,80
IncobotulinumtoxinA is a safe and effective agent, compared
with placebo, for the treatment of patients with CD or BSP
and is noninferior to onabotulinumtoxinA. Based on the
results of clinical trials, incobotulinumtoxinA is indicated
in the United States for the treatment of adults with CD and
for the treatment of BSP in adults previously treated with
onabotulinumtoxinA. The absence of complexing proteins
in this formulation of BoNT/A does not seem to confer any
differences in preinjection stability, risk for diffusion outside
of target muscles, or time course of response following
injection. By contrast, the risk for immunogenicity and possible
treatment failure may be lower than that with other
formulations. However, additional long-term clinical data regarding
immunogenicity are warranted.
The author thanks the Curry Rockefeller Group for editorial
assistance in preparing this manuscript for publication.
The author has received honoraria for speaking and
consulting with Allergan, Inc and for consulting with Merz
submit your manuscript | www.dovepress.com
submit your manuscript | www.dovepress.com
Publish your work in this journal
Neuropsychiatric Disease and Treatment is an international,
peerreviewed journal of clinical therapeutics and pharmacology focusing
on concise rapid reporting of clinical or pre-clinical studies on a
range of neuropsychiatric and neurological disorders. This journal
is indexed on PubMed Central, the ‘PsycINFO’ database and CAS.
1. Tarsy D , Simon DK. Dystonia. N Engl J Med . 2006 ; 355 ( 8 ): 818 - 829 .
2. Tanabe LM , Kim CE , Alagem N , Dauer WT . Primary dystonia: molecules and mechanisms . Nat Rev Neurol . 2009 ; 5 ( 11 ): 598 - 609 .
3. Neychev VK , Fan X , Mitev VI , Hess EJ , Jinna HA . The basal ganglia and cerebellum interact in the expression of dystonic movement . Brain . 2008 ; 131 (Pt 9): 2499 - 2509 .
4. Zoons E , Booij J , Nederveen AJ , Dijk JM , Tijssen MA . Structural, functional and molecular imaging of the brain in primary focal dystonia-A review . Neuroimage . 2011 ; 56 ( 3 ): 1011 - 1020 .
5. Vidailhet M , Grabli D , Roze E . Pathophysiology of dystonia. Curr Opin Neurol . 2009 ; 22 ( 4 ): 406 - 413 .
6. Albanese A , Barnes MP , Bhatia KP , et al. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force . Eur J Neurol . 2006 ; 13 ( 5 ): 433 - 444 .
7. Nutt JG , Muenter MD , Aronson A , Kurland LT , Melton LJ 3rd. Epidemiology of focal and generalized dystonia in Rochester, Minnesota . Mov Disord . 1988 ; 3 ( 3 ): 188 - 194 .
8. Duffey PO , Butler AG , Hawthorne MT , Barnes MP . The epidemiology of the primary dystonias in the north of England . Adv Neurol . 1998 ; 78 : 121 - 125 .
9. Greene P , Kang UJ , Fahn S. Spread of symptoms in idiopathic torsion dystonia . Mov Disord . 1995 ; 10 ( 2 ): 143 - 152 .
10. Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group. A prevalence study of primary dystonia in eight European countries . J Neurol . 2000 ; 247 ( 10 ): 787 - 792 .
11. Papantonio AM , Beghi E , Fogli D , et al. Prevalence of primary focal or segmental dystonia in adults in the district of Foggia, southern Italy: a service-based study . Neuroepidemiology . 2009 ; 33 ( 2 ): 117 - 123 .
12. Matsumoto S , Nishimura M , Shibassaki H , Kaji R . Epidemiology of primary dystonias in Japan: comparison with Western countries . Mov Disord . 2003 ; 18 ( 10 ): 1196 - 1198 .
13. Sugawara M , Watanabe S , Toyoshima I. Prevalence of dystonia in Akita Prefecture in Northern Japan . Mov Disord . 2006 ; 21 ( 7 ): 1047 - 1049 .
14. Cossu G , Mereu A , Deriu M , et al. Prevalence of primary blepharospasm in Sardinia, Italy: a service-based survey . Mov Disord . 2006 ; 21 ( 11 ): 2005 - 2008 .
15. Chan J , Brin MF , Fahn S. Idiopathic cervical dystonia: clinical characteristics . Mov Disord . 1991 ; 6 ( 2 ): 119 - 126 .
16. Dauer WT , Burke RE , Greene P , Fahn S. Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia . Brain . 1998 ; 121 (Pt 4): 547 - 560 .
17. Jankovic J , Kenney C , Grafe S , Goertelmeyer R , Comes G. Relationship between various clinical outcome assessments in patients with blepharospasm . Mov Disord . 2009 ; 24 ( 3 ): 407 - 413 .
18. Müller J , Kemmler G , Wissel J , et al; Austrian Botulinum Toxin and Dystonia Study Group. The impact of blepharospasm and cervical dystonia on health-related quality of life and depression . J Neurol . 2002 ; 249 ( 7 ): 842 - 846 .
19. Lim VK . Health related quality of life in patients with dystonia and their caregivers in New Zealand and Australia . Mov Disord . 2007 ; 22 ( 7 ): 998 - 1103 .
20. Jankovic J , Leder S , Warner D , Schwartz K. Cervical dystonia: clinical findings and associated movement disorders . Neurology . 1991 ; 41 ( 7 ): 1088 - 1091 .
21. Grandas F , Elston J , Quinn N , Marsden CD . Blepharospasm: a review of 264 patients . J Neurol Neurosurg Psychiatry . 1988 ; 51 ( 6 ): 767 - 772 .
22. Jankovic J , Havins WE , Wilkins RB . Blinking and blepharospasm. Mechanism, diagnosis, and management . JAMA . 1982 ; 248 ( 23 ): 3160 - 3164 .
23. Martino D , Liuzzi D , Macerollo A , Aniello MS , Livrea P , Defazio G. The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia . Mov Disord . 2010 ; 25 ( 4 ): 407 - 412 .
24. O 'Riordan S , Raymond D , Lynch T , et al. Age at onset as a factor in determining the phenotype of primary torsion dystonia . Neurology . 2004 ; 63 ( 8 ): 1423 - 1426 .
25. Defazio G , Berardelli A , Hallett M. Do primary adult-onset focal dystonias share aetiological factors? Brain . 2007 ; 130 (Pt 5): 1183 - 1193 .
26. H a u s s e r m a n n P, M a r c z o c h S , K l i n g e r C , L a n d g r e b e M , Conrad B , Ceballos-Bauman A . Long-term follow-up of cervical dystonia patients treated with botulinum toxin A . Mov Disord. 2004 ; 19 ( 3 ): 303 - 308 .
27. Weiss EM , Hershey T , Karimi M , et al. Relative risk of spread of symptoms among the focal onset primary dystonias . Mov Disord . 2006 ; 21 ( 8 ): 1175 - 1181 .
28. Hierholzer J , Cordes M , Schelosky L , et al. Dopamine D2 receptor imaging with iodine-123-iodobenzamide SPECT in idiopathic rotational torticollis . J Nucl Med . 1994 ; 35 ( 12 ): 1921 - 1927 .
29. Perlmutter JS , Stambuk MK , Markham J , et al. Decreased [18F] spiperone binding in putamen in idiopathic focal dystonia . J Neurosci . 1997 ; 17 ( 2 ): 843 - 850 .
30. Naumann M , Pirker W , Reiners K , Lange KW , Becker G , Brücke T. Imaging the pre- and postsynaptic side of striatal dopaminergic synapses in idiopathic cervical dystonia: a SPECT study using [123I] epidepride and [123I] beta-CIT . Mov Disord . 1998 ; 13 ( 2 ): 319 - 323 .
31. Karimi M , Moerlein SM , Videen TO , et al. Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect? Mov Disord . 2011 ; 26 ( 1 ): 100 - 106 .
32. Pauletti G , Berardelli A , Cruccu G , Agostino R , Manfredi M. Blink reflex and the masseter inhibitory reflex in patients with dystonia . Mov Disord . 1993 ; 8 ( 4 ): 495 - 500 .
33. Tolosa E , Montserrat L , Bayes A . Blink reflex studies in focal dystonias: enhanced excitability of brainstem interneurons in cranial dystonia and spasmodic torticollis . Mov Disord . 1988 ; 3 ( 1 ): 61 - 69 .
34. Berardelli A , Rothwell JC , Day BL , Marsden CD . Pathophysiology of blepharospasm and oromandibular dystonia . Brain . 1985 ; 108 (Pt 3): 593 - 608 .
35. Rinnerthaler M , Benecke C , Bartha L , Entner T , Poewe W , Mueller J . Facial recognition in primary focal dystonia . Mov Disord . 2006 ; 21 ( 1 ): 78 - 82 .
36. Molloy FM , Carr TD , Zeuner KE , Dambrosia JM , Hallett M. Abnormalities of spatial discrimination in focal and generalized dystonia . Brain . 2003 ; 126 (Pt 10): 2175 - 2182 .
37. Obermann M , Yaldizli O , De Greiff A , et al. Morphometric changes of sensorimotor structures in focal dystonia . Mov Disord . 2007 ; 22 ( 8 ): 1117 - 1123 .
38. Albanese A , Asmus F , Bhatia KP , et al. EFNS guidelines on diagnosis and treatment of primary dystonias . Eur J Neurol . 2011 ; 18 ( 1 ): 5 - 18 .
39. Simpson DM , Blitzer A , Brashear A , et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology . Neurology. 2008 ; 70 ( 19 ): 1699 - 1706 .
40. Jankovic J . Botulinum toxin in clinical practice . J Neurol Neurosurg Psychiatry . 2004 ; 75 ( 7 ): 951 - 957 .
41. Adam OR , Jankovic J . Treatment of dystonia . Parkinsonism Relat Disord . 2007 ; 13 ( Suppl 3 ): S362 - S368 .
42. Albanese A . Terminology for preparations of botulinum toxins: what a difference a name makes . JAMA . 2011 ; 305 ( 1 ): 89 - 90 .
43. Wenzel R , Jones D , Borrego JA . Comparing two botulinum toxin type A formulations using manufacturers' product summaries . J Clin Pharm Ther . 2007 ; 32 ( 4 ): 387 - 402 .
44. Comella C , Jankovic J , Shannon KM , et al; Dystonia Study Group. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia . Neurology . 2005 ; 65 ( 9 ): 1423 - 1429 .
45. Pappert EJ , Germanson T ; Myobloc/Neurobloc European Cervical Dystonia Study Group. Botulinum toxin type B vs type A in toxinnaïve patients with cervical dystonia: randomized, double-blind, noninferiority trial . Mov Disord . 2008 ; 23 ( 4 ): 510 - 517 .
46. Hallett M , Benecke R , Blitzer A , Comella CL . Treatment of focal dystonias with botulinum neurotoxin . Toxicon . 2009 ; 54 ( 5 ): 628 - 633 .
47. Sampaio C , Ferreira JJ , Simões F , et al. DYSBOT: a single-blind, randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A - Dysport and Botox - assuming a ratio of 4:1 . Mov Disord . 1997 ; 12 ( 6 ): 1013 - 1018 .
48. Odergren T , Hjaltason H , Kaakkola S , et al. A double-blind, randomised, parallel group study to investigate the dose equivalence of Dysport® and Botox® in the treatment of cervical dystonia . J Neurol Neurosurg Psychiatry . 1998 ; 64 ( 1 ): 6 - 12 .
49. Ranoux D , Gury C , Fondarai J , Mas JL , Zuber M. Respective potencies of Botox and Dysport: a double-blind, randomised, crossover study in cervical dystonia . J Neurol Neurosurg Psychiatry . 2002 ; 72 ( 4 ): 459 - 462 .
50. Nüssgens Z , Roggenkämper P . Comparison of two botulinum-toxin preparations in the treatment of essential blepharospasm . Graefes Arch Clin Exp Ophthalmol . 1997 ; 235 ( 4 ): 197 - 199 .
51. Benecke R , Jost WH , Kanovsky P , Ruzicka E , Comes G , Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia . Neurology . 2005 ; 64 ( 11 ): 1949 - 1951 .
52. Jankovic J , Vuong KD , Ahsan J . Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia . Neurology . 2003 ; 60 ( 7 ): 1186 - 1188 .
53. Dressler D , Hallett M. Immunological aspects of Botox®, Dysport® and Myobloc™/Neurobloc®. Eur J Neurol . 2006 ; 13 Suppl 1 : 11 - 15 .
54. Dressler D , Bigalke H . Botulinum toxin type B de novo therapy of cervical dystonia: frequency of antibody induced therapy failure . J Neurol . 2005 ; 252 ( 8 ): 904 - 907 .
55. Brin MF , Comella CL , Jankovic J , Lai F , Naumann M ; CD-017 BoNTA Study Group. Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay . Mov Disord . 2008 ; 23 ( 10 ): 1353 - 1360 .
56. Dressler D , Bigalke H , Benecke R . Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure . J Neurol . 2003 ; 250 ( 8 ): 967 - 969 .
57. Frevert J , Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics . 2010 ; 4 : 325 - 332 .
58. Hauser D , Eklund MW , Boquet P , Popoff MR . Organization of the botulinum neurotoxin C1 gene and its associated non-toxic protein genes in Clostridium botulinum C 468 . Mol Gen Genet . 1994 ; 243 ( 6 ): 631 - 640 .
59. Minton NP . Molecular genetics of clostridial neurotoxins . Curr Top Microbiol Immunol . 1995 ; 195 : 161 - 194 .
60. Ohishi I , Sugii S , Sakaguchi G . Oral toxicities of Clostridium botulinum toxins in response to molecular size . Infect Immun . 1977 ; 16 ( 1 ): 107 - 109 .
61. Ohishi I , Sakaguchi G . Oral toxicities of Clostridium botulinum type C and D toxins of different molecular sizes . Infect Immun . 1980 ; 28 ( 2 ): 303 - 309 .
62. Aoki KR , Ranoux D , Wissel J . Using translational medicine to understand clinical differences between botulinum toxin formulations . Eur J Neurol . 2006 ; 13 Suppl 4 : 10 - 19 .
63. Zhou Y , Foss S , Lindo P , Sarkar H , Singh BR . Hemagglutinin-33 of type A botulinum neurotoxin complex binds with synaptotagmin II . FEBS J . 2005 ; 272 ( 11 ): 2717 - 2726 .
64. Eisele KH , Fink K , Vey M , Taylor HV . Studies on the dissociation of botulinum toxin type A complexes . Toxicon . 2011 ; 57 ( 4 ): 555 - 565 .
65. Frevert J . Xeomin is free from complexing proteins . Toxicon . 2009 ; 54 ( 5 ): 697 - 701 .
66. Panjwani N , O'Keefe R , Pickett A . Biochemical, functional and potency characteristics of type A botulinum toxin in clinical use . Botulinum J . 2008 ; 1 ( 1 ): 153 - 166 .
67. Dodd SL , Rowell BA , Vrabas IS , Arrowsmith RJ , Weatherill PJ . A comparison of the spread of three formulations of botulinum neurotoxin A as determined by effects on muscle function . Eur J Neurol . 1998 ; 5 ( 2 ): 181 - 186 .
68. Wohlfarth K , Müller C , Sassin I , Comes G , Grafe S. Neurophysiological double-blind trial of a botulinum neurotoxin type A free of complexing proteins . Clin Neuropharmacol . 2007 ; 30 ( 2 ): 86 - 94 .
69. Kukreja R , Chang TW , Cal S , et al. Immunological characterization of the subunits of type A botulinum neurotoxin and different components of its associated proteins . Toxicon . 2009 ; 53 ( 6 ): 616 - 624 .
70. Singh BR , Lopez T , Silvia MA . Immunological characterization of type A botulinum neurotoxin in its purified and complexed forms . Toxicon . 1996 ; 34 ( 2 ): 267 - 275 .
71. Sharma SK , Singh BR . Immunological properties of Hn-33 purified from type A Clostridium botulinum . J Nat Toxins . 2000 ; 9 ( 4 ): 357 - 362 .
72. Lange O , Bigalke H , Dengler R , Wegner F , deGroot M , Wohlfarth K. Neutralizing antibodies and secondary therapy failure after treatment with botulinum toxin type A: much ado about nothing? Clin Neuropharmacol . 2009 ; 32 ( 4 ): 213 - 218 .
73. Xeomin (incobotulinumtoxinA). Prescribing information . 2010 . Available from: http://www.xeomin.com/files/Xeomin_PI.pdf. Accessed May 2 , 2011 .
74. Dressler D , Benecke R . Pharmacology of therapeutic botulinum toxin preparations . Disabil Rehabil . 2007 ; 29 ( 23 ): 1761 - 1768 .
75. Borodic GE , Ferrante R , Pearce LB , Smith K. Histologic assessment of dose-related diffusion and muscle fiber response after therapeutic botulinum A toxin injection . Mov Disord . 1994 ; 9 ( 1 ): 31 - 39 .
76. Poewe W , Deuschl G , Nebe A , et al; German Dystonia Study Group. What is the optimal dose of botulinum toxin A in the treatment of cervical dystonia? Results of a double blind, placebo controlled, dose ranging study using Dysport® . J Neurol Neurosurg Psychiatry . 1998 ; 64 ( 1 ): 13 - 17 .
77. Brashear A , Lew MF , Dykstra DD , et al. Safety and eff icacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia . Neurology . 1999 ; 53 ( 7 ): 1439 - 1446 .
78. ICH Q1A(R2) Guideline. Stability testing of new drug substances and products . 2003 . Available from: http://www.fda.gov/downloads/ regulatoryinformation/guidances/ucm128204.pdf. Accessed Nov 3 , 2011 .
79. Grein S , Fink K. Complexing proteins are not required for stability of Botulinum neurotoxin type A preparations. Poster presented at: 71st Annual Assembly of the American Academy of Physical Medicine and Rehabilitation (AAPM &R); November 4-7 , 2010 ; Seattle, WA. Poster P106.
80. Jost WH , Blümel J , Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN®) in focal dystonia . Drugs . 2007 ; 67 ( 5 ): 669 - 683 .
81. Jost WH , Kohl A , Brinkmann S , Comes G . Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT 201) compared with commercially available botulinum toxin type A (Botox®) in healthy volunteers . J Neural Transm . 2005 ; 112 ( 7 ): 905 - 913 .
82. Benecke R. Xeomin in the treatment of cervical dystonia . Eur J Neurol . 2009 ; 16 Suppl 2 : S6 - S10 .
83. Consky ES , Lang AE. Clinical assessments of patients with cervical dystonia . In: Jankovic J , Hallett M , editors. Therapy with Botulinum Toxin . New York, NY: Marcel Dekker; 1994 : 211 - 237 .
84. Comella CL , Jankovic J , Truong DD , Hanschmann A , Grafe S ; on behalf of the US XEOMIN Cervical Dystonia Study Group . Efficacy and safety of incobotulinumtoxinA (NT 201, XEOMIN®, botulinum neurotoxin type A, without accessory proteins) in patients with cervical dystonia . J Neurol Sci . 2011 ; 308 ( 1-2 ): 103 - 109 .
85. Botox (onabotulinumtoxinA). Prescribing information . 2010 . Available from: http://www.allergan.com/assets/pdf/botox_pi.pdf. Accessed May 2 , 2011 .
86. Grafe S , Comella C , Jankovic J , Truong D , Hanschmann A . Efficacy and safety of NT 201 (botulinum neurotoxin type A free from complexing proteins) in treatment-naïve cervical dystonia patients [abstract] . Mov Disord . 2009 ; 24 ( Suppl 1 ): S92 - S93 :Tu- 401 .
87. Grafe S , Comella C , Jankovic J , Truong D , Hanschmann A . Efficacy and safety of NT 201 (botulinum neurotoxin type A free from complexing proteins) in pre-treated cervical dystonia patients [abstract] . Mov Disord . 2009 ; 24 ( Suppl 1 ):S92:Tu- 400 .
88. Grafe S , Hanschmann A . Safety and efficacy of repeated NT 201 (botulinum neurotoxin type A free from complexing proteins) injections of patients with cervical dystonia: a first long-term safety analysis [abstract] . Neurology . 2010 ; 74 ( 9 Suppl 2 ):A88: P01 . 270 .
89. Roggenkämper P , Jost WH , Bihari K , Comes G , Grafe S ; NT 201 Blepharospasm Study Team. Efficacy and safety of a new Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm . J Neural Transm . 2006 ; 113 ( 3 ): 303 - 312 .
90. Wissel J , Müller J , Dressnandt J , et al. Management of spasticity associated pain with botulinum toxin A . J Pain Symptom Manage . 2000 ; 20 ( 1 ): 44 - 49 .
91. Endicott J , Spitzer RL , Fleiss JL , Cohen J . The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance . Arch Gen Psychiatry . 1976 ; 33 ( 6 ): 766 - 771 .
92. Wabbels B , Reichel G , Fulford-Smith A , Wright N , Roggenkämper P . Double-blind, randomised, parallel group pilot study comparing two botulinum toxin type A products for the treatment of blepharospasm . J Neural Transm . 2011 ; 118 ( 2 ): 233 - 239 .
93. Jankovic J , Comella C , Hanschmann A , Grafe S. Efficacy and safety of incobotulinumtoxinA (NT 201, Xeomin) in the treatment of blepharospasm-A randomized trial . Mov Disord . 2011 ; 26 ( 8 ): 1521 - 1528 .
94. Benecke R , Grafe S , Sassin I , Comes G . Overall clinical efficacy and overall tolerability of NT 201; botulinum neurotoxin free from complexing proteins [abstract] . Mov Disord . 2009 ; 24 ( Suppl S1 ): S84 :Mo- 403 .
95. Grafe S , Hanschmann A . Safety and efficacy of repeated NT 201 (botulinum neurotoxin type A free from complexing proteins) injections of patients with focal dystonia [abstract] . Neurology . 2010 ; 74 ( 9 Suppl 2 ):A87: P01 . 268 .