Clinical Pharmacology of Botulinum Toxin

Drugs

Dirk Dressler

Contents
1 Introduction
2 Therapeutic Mode of Action
3 Time Course of Action
4 Target Tissues
5 General Pharmacological Profile
6 Adverse Effects
7 Interactions
8 Potency Labelling
9 Antigenicity
10 Therapeutic Preparations
References

Abstract
Botulinum toxin (BT) has changed from a deadly poison to a novel therapeutic
principle for a large number of disorders in many medical areas.
BT drugs are special in many ways: they are biologicals, their active ingredient
BT is not patentable, their spectrum of clinical applications is extremely broad,
their dose range is enormous, their mode of action is local and their life cycles are
special.
This review covers BT’s therapeutic mode of action, time course of action,
target tissues, pharmacological profile, adverse effects, interactions, potency
labelling and antigenicity as well as BT’s therapeutic preparations.

D. Dressler (*)
Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover,
Germany
e-mail: dressler.dirk@mh-hannover.de

# Springer Nature Switzerland AG 2019

Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2019_273
 D. Dressler

Keywords
Adverse effects · Antigenicity · Botulinum toxin · Clinical pharmacology ·
Interactions · Mode of action · Pharmacological profile · Potency labelling ·
Target tissues · Therapeutic preparations · Time course

1 Introduction

Botulinum toxin (BT) has made one of the most remarkable transitions in the
history of mankind: once infamous as a food safety hazard and a means of biological
warfare it is now a drug for a large number of disorders for many of which it has
revolutionised their treatment.
BT drugs are special in many ways: As biologicals they are not only specified by
their chemicophysical properties alone, but also by their steric confirmation which is
heavily influenced by the manufacturing process and handling conditions. Compar-
ing biologicals is challenging and has to consider many parameters. Nevertheless,
also biologicals can and need to be compared with respect to efficacy, adverse effects
and economics. BT as a natural compound cannot be protected by patents. Intellec-
tual property protection is mainly gained by the BT drug’s registration status. This
generates very special drug life cycles and the option of alternative registration
pathways through biosimilarity approval. This may dramatically influence the future
development of BT drugs. The broad spectrum of clinical applications generates
enormous dose ranges leading to serious pricing issues. As a strictly local agent BT
drugs require specific registration pathways.
This review covers BT’s therapeutic mode of action, time course of action, target
tissues, pharmacological profile, adverse effects, interactions, potency labelling and
antigenicity as well as BT’s therapeutic preparations.

2 Therapeutic Mode of Action

Botulinum neurotoxin (BNT) is blocking the SNARE protein-mediated excretion

process of acetylcholine from cholinergic neurons. BT’s binding, internalisation and
intracellular action involve highly complex and specific molecular mechanisms
(Dressler and Foster 2018). The BT-induced cholinergic blockade is long-lasting,
but temporary and fully reversible and does not produce any structural damage even
in delicate tissues and after prolonged application. It reduces the activity of the
cholinergic neuromuscular junction and of the cholinergic autonomic junction
through interaction with the cholinergic nerve terminal, i.e. the peripheral nervous
system. Additional effects on pain perception and pain processing have been
described and a registration to treat chronic migraine has subsequently been granted
(Aurora et al. 2010; Diener et al. 2010). Interactions with calcitonin-gene-related
peptide (CGRP) and other transmitters have been proposed. Exact mechanisms
involved, however, are largely unknown, but would – most likely – involve direct
central nervous system interactions. It has long been known that BT does not only
interact with the SNARE proteins in the nerve terminals but can also be transported
Clinical Pharmacology of Botulinum Toxin Drugs

to the alpha motoneuron’s soma by retrograde axonal transport (Wiegand et al.

1976). Recent evidence suggests that BT – like the structurally closely related
tetanus toxin – might be able to transgress to secondary neurons (Antonucci et al.
2008). This would require an externalisation process equally complex as BT’s
internalisation process. So far, nothing is known about such a process. Indirect
central nervous system effects are not surprisingly numerous as BT’s peripheral
effect on the human body is considerable. As BT was demonstrated to interact not
only with striate or smooth muscle fibres but also with the intrafusal muscle fibres of
the Golgi muscle tendon organ (Filippi et al. 1993; Dressler et al. 1993; Rosales et al.
1996), additional therapeutic effects on muscle hyperactivity syndromes beyond the
well-described peripheral paresis were discussed. Recently, antidepressive effects of
BT application have been described (Wollmer et al. 2012). Even more so than in
analgesia, underlying mechanisms remain unclear and central as well as peripheral
nervous system effects have been discussed.

3 Time Course of Action

BT has a prolonged biological effect. This is one of the key prerequisites for its
therapeutic use. BT drug effects follow a distinct time course (Dressler and Benecke
2007). With a delay of 2–5 days, their therapeutic effect builds up (build-up phase),
stays on a plateau for 6–10 weeks (plateau phase) and then gradually declines
(wearing-off phase). To maintain a steady clinical improvement, reinjections
become necessary. This is usually the case after 8–14 weeks, but may be delayed
in reality by many considerations including the physician’s availability, travel
logistics, economic considerations and the patient’s personal choices.
Different BT types have different durations of action. Exact data on the duration
of action of BT in humans is sparse, as in most treatment studies patients would not
accept reinjection delays once they enter the wearing-off phase. In humans, BT-A
has the longest duration of action, whereas BT-B may have a slightly shorter one and
BT type C and BT type E seem to have a particularly short duration of action
(Dressler and Foster 2018). BT’s duration of action may also depend on the
particular target tissue chosen. BT therapy of hyperhidrosis, where it is applied to
the sweat glands, may produce somewhat longer effects than BT therapy of muscle
hyperactivity syndromes (Naumann and Jost 2004). Comparing the therapeutic
duration of action requires identical endpoint definitions and identical treatment
parameters, so that valid data on the duration of action of different BT types or
different BT drugs can only be generated by direct head-to-head comparison studies.
The build-up phase is therapeutically less relevant as it only occurs in full at the
initiation of BT therapy and as it is very short in relation to the plateau phase.
Different BT types do not seem to have much different build-up phases. The same
seems to be true for the wearing-off phase. Long-term data show that the temporal
profile of BT’s action is remarkably stable over even decade-long applications
(Dressler et al. 2015b). This lack of enzymatic induction and lack of tachyphylaxis
are other key prerequisites for BT’s therapeutic use.
 D. Dressler

BT’s effect follows a dose-effect correlation and a dose-duration correlation.

With the dose-effect correlation (Dressler and Rothwell 2000), it is possible to
adjust therapeutic BT doses to the effect size necessary. Dose-effect curves can
also be used to detect BT antibodies (Dressler et al. 2000) and to compare BT drug
potencies (Dressler et al. 2018). The dose-duration correlation is weak. With usual
BT doses applied, the duration effect is in most cases saturated.

4 Target Tissues

BT drugs can be applied to all tissues with cholinergic innervation including muscle
tissue (striate and smooth), exocrine glandular tissue (sweat glands, saliva gland,
lacrimal glands) and pain relevant structures. The target tissue affinity seems to be
the same for BT drugs of the same BT type, but is different between BT drugs of
different BT types. Whereas BT-A has a relatively strong affinity to muscle tissue
and a relatively weak one to autonomic tissue, this relationship is reversed in BT-B
(Dressler and Benecke 2003). Potentially different durations of action in different
target tissues have been discussed above.

5 General Pharmacological Profile

With all features described above, BT drugs can be characterised as long-term and
long-lasting, but temporary and fully reversible, well controllable, local and – even
in very high doses – surprisingly safe drugs for muscle relaxation, exocrine gland
secretion suppression and analgesia.

6 Adverse Effects

The adverse effect profile of BT is remarkably benign, as BT remains at its injection

site and does not participate in the body’s general metabolism thus sparing critical
absorption and secretion organs. Adverse effects of BT therapy include unwanted
paresis and unwanted exocrine gland suppression. All adverse effects are acute only.
They may be divided in local and systemic ones. Local adverse effects are caused by
BT spread from the target tissue into adjacent tissues. Systemic adverse effects occur
when relevant amounts of BT are distributed with the bloodstream producing effects
which cannot be explained by local BT spread. As the fraction of BT which is not
bound to the target tissue is very low (Takamizawa et al. 1986), systemic adverse
effects would require application of substantial doses. Recently, BT high-dose
therapy was introduced (Dressler et al. 2015a, b) and subsequently reconfirmed
(Wissel et al. 2017). With high-dose therapy total incobotulinumtoxinA doses of up
to 1250MU reconstituted with 2.5 ml of 0.9% NaCl/H2O, distributed over a large
number of target muscles and using several injection sites per target muscle are
applied. Acute and long-term follow-up demonstrated not only safety with respect to
Clinical Pharmacology of Botulinum Toxin Drugs

systemic toxicity but also safety with respect of BT antibody formation (Dressler
et al. 2015a). With this, the therapeutic dose range of BT is now considerable and
allows treatment not only of focal muscle hyperactivity disorders but also of
segmental and generalised ones, thus advancing BT therapy considerably (Dressler
et al. 2016b). Repeated BT therapy – often for decades – does not produce additional
adverse effects indicating also an exceptional long-term safety (Dressler et al. 2013).
The adverse effect profile of BT-B is much different from that of BT-A drugs.
Even at moderate BT-B doses, patients may experience anticholinergic adverse
effects including dryness of mouth, dryness of eyes and accommodation difficulties
(Dressler and Benecke 2004).

7 Interactions

Registration documents warn not to perform BT therapy in the presence of

anticoagulation. However, it was recently shown that BT therapy can be performed
safely as long as thin injection needles are used (Schrader et al. 2018). It is strongly
advised not to interrupt coagulation in preparation of BT therapy as this may greatly
increase the risk of thrombosis or haemorrhage. Underlying neuromuscular trans-
mission disorders including Lambert-Eaton myasthenic syndrome and myasthenia
gravis may increase the sensitivity to BT therapy (Dressler 2010; Erbguth et al.
1993), but are no contraindications as long as BT doses are adjusted accordingly. In
case of unusual hypersensitivity towards BT therapy, hitherto undetected underlying
neuromuscular transmission disorders should be considered.

8 Potency Labelling

According to the European Pharmacopoeia, the biological potency of BT drugs is

measured by a standardised LD50 assay and expressed in mouse units (European
Pharmacopoeia 2008a, b). However, clinical practise suggests that the potency
labelling of different BT type A drugs is not identical. Between the potency labelling
of Botox® and Dysport® conversion factors from 1:5 to 1:2.41 have been reported in
clinical studies (Brin and Blitzer 1993; Marion et al. 1995; Marsden 1993; Van den
Berg et al. 1996; Ranoux et al. 2002). In LD50 assays conversion factors of 1:2.89
(Pickett and Hambleton 1994), 1:2.86 (Van den Berg et al. 1996) and 1:1.9 (First
et al. 1994) were determined. Between the potency labelling of Xeomin® and
Botox® a conversion factor of 1:1 is established (Dressler 2009; Dressler et al.
2012, 2018; Scaglione 2016). The conversion factor between the BT-A drug
Botox® and the BT-B drug Myobloc® seems to be 1:40. Reasons for the contradic-
tory potency labelling are unclear, but may include differences in the potency assays
(for BT-A drug differences) and different species susceptibilities (for BT-A and
BT-B drug differences). Clinical studies to determine the conversion factors between
different BT drugs are usually of limited validity, especially when clinical models
with limited sensitivity and low adverse effect frequencies as in blepharospasm and
 D. Dressler

small sample sizes are used. To obtain more precise results, full dose-effect curves
need to be compared.

9 Antigenicity

The current understanding of BT antigenicity was recently reviewed (Dressler and

Bigalke 2017a). As BNT is a protein, antigenicity of BT drugs has always been a
concern. After it was believed that BNT amounts applied were too small to induce
immune responses, it became clear in the early 1990s that even the minute therapeu-
tic BNT doses can induce BT antibody formation reducing BNT’s therapeutic effects
and adverse effects. Although the actual frequency of complete antibody-induced
therapy failure is – as will be subsequently described – low, measures to prevent it
include reducing BT dosages, and interinjection intervals are considerably limiting
the real potential of BT therapy. Reducing antigenicity in BT therapy should,
therefore, be an important development goal.

BT Antibodies BT antibodies can be neutralising, i.e. blocking BNT’s mode of

action, and they can be non-neutralising, i.e. targeting non-functional BNT epitopes,
indicating high BT antibody specificity. BT antibodies may occur in different titres
(Dressler et al. 2002). Those titres may be very low and may not reduce BT’s
therapeutic effects, thus making them therapeutically irrelevant. When titres are
intermediate, they may produce partial therapy failure. High titres elicit complete
therapy failure. As also the amount of BNT applied is relevant (Dressler et al. 2002),
we described the interaction between BNT and BT antibodies as a balance indicating
the importance of BT antibody titre determination.

BT Antibody Detection Detection of BT antibodies bears numerous risks of

misinterpretation concerning test system sensitivity and specificity and the underly-
ing balance model. BT antibodies can be detected by structural tests using ELISA
arrays (Dressler et al. 2014). They are not able to distinguish between neutralising
and non-neutralising antibodies. Antibodies can also be detected by functional tests
detecting only neutralising ones. In principle, all biological BNT effects can be used
in a test system. Usually, lethality is used in animal tests. The mouse diaphragm
assay is an advanced and animal friendly ex vivo test with an elaborate quality
assessment (Goeschel et al. 1997). In humans usually paretic effects are used as in
the EDB test (Kessler and Benecke 1997) or the SCM test (Dressler et al. 2000).
However, also sweating may be a test parameter.

Interpretation of BT Antibody Measurements Results from BT antibody tests

need to be interpreted carefully. Demonstrating the shear presence of BT antibodies
is usually not helpful, as they may present false-positive results, results from
hypersensitive test systems and as they may not be correlated to clinical
nonresponsiveness. Only quantitative measurements of BT antibody titres generate
data for exact clinical interpretation.
Clinical Pharmacology of Botulinum Toxin Drugs

Risk Factors for BT Antibody Formation Classical risk factors are the single
dose, i.e. the amount of BNT applied at each injection series; the interinjection
interval, i.e. the time between two subsequent injection series; and the application of
booster injections, i.e. two BT injection series with an interinjection interval of less
than 2 weeks. More recently, it became clear that also the immunological quality of
the BT drug used as described by the specific biological potency may be a risk factor
(Dressler and Bigalke 2017a). Sex and age of the patients treated, the cumulative BT
dose applied and the treatment duration do not seem to be risk factors. Also, so far,
there is no indication that the particular target tissue injected may change the risk of
BT antibody formation.

Occurrence of BT Antibodies There are no exact data on the frequency of

BT antibody formation available, as they would require prospective monitoring
of large patient groups over prolonged periods of time. Interestingly, BT antibody
formation seems to occur in a time window early in the treatment (Dressler
2004). After several years of BT therapy, the risk for BT antibody formation actually
seems to drop (Dressler 2004). Estimates suggest that complete antibody-induced
therapy failure for low- to intermediate-dose indications has a frequency of
1–5% when onabotulinumtoxinA and abobotulinumtoxinA are used. When
rimabotulinumtoxinA is used this frequency may go up to 40% (Dressler and
Bigalke 2005). For incobotulinumtoxinA there have not been any reports on com-
plete antibody-induced therapy failure, although this BT drug has been worldwide
available since 2005. This low – or even non-existent – antigenicity was the basis to
improve the BT treatment algorithms by introducing the short interval therapy
(Dressler and Adib Saberi 2017a) and the high-dose therapy (Dressler et al.
2015a, b), thus improving BT therapy considerably. The particular aetiology of the
muscle hyperactivity syndrome treated and the target tissue type do not seem to
matter.

10 Therapeutic Preparations

BT drugs are complex mixtures of compounds. Their various features are shown in
Table 1. BT drugs consist of BNT, complexing proteins (CP) and excipients.

BNT BNT is the therapeutically active ingredient. It exists in seven different

subtypes named type A to type G. BNT used in BT drugs is either BT type A
(BT-A) or BT type B (BT-B). BT types E, C, D and F have only experimentally been
used in humans. Therapeutically relevant parameters of different BT types may
differ considerably, whereas BT drugs of the same BT type produce very similar
effects as they are based on virtually identical BNT. As described above, BT
subtypes are different with respect to target tissue affinity, antigenicity and time
course of action.
 D. Dressler

Table 1 Features of botulinum toxin drugs

Botulinum neurotoxin Subtype
Target tissue affinity
Antigenicity
Time course of action
Duration of action
Latency of onset
Complexing proteins Presence or removal
Antigenicity
Excipients Human serum albumin, gelatine, polysorbate
Risk of HIV, BSE, anaphylaxis
Others
pH value
Manufacturing process Production continuity
Aliquotation, continuous production
Purification
Crystallisation, dialysis, chromatography,
Precipitation, High-Pure technology
Activation
Specific biological activity
Degree of BNT inactivation during purification
Degree of knicking during activation
Potency testing
Animal-based assays, cell-based assays
Potency consistency
Stabilisation
Lyophilisation (freeze drying), vacuum drying, pH
Reduction
Potency stability
Unreconstituted, reconstituted drug
Potency labelling
Manufacturer’s support Product documentation
Product support
Reliability of drug supply
Counterfeit protection
Handling safety
Differentiability of vials with different potencies
Denomination of packaging size
Potency per vial
Packages per over-pack
Competitive pricing per adjusted mouse unit

CP CP are a residue of the natural development process and are not necessary for
BT’s therapeutic action. Their role in BT’s antigenicity is unclear. It was suggested
they may indirectly increase BT’s antigenicity by attracting leucocytes into the
injection area (Lee et al. 2005). Based on these considerations, CP have been
removed from the BT drug incobotulinumtoxinA without changing its therapeutic
and adverse effect profile, but potentially contributing to its particularly low
antigenicity.
Clinical Pharmacology of Botulinum Toxin Drugs

Excipients Excipients are added during the manufacturing process to stabilise BT

drugs. Usually, they contain human serum albumin, but lanbotulinumtoxinA
contains bovine gelatine instead and Coretox® uses polysorbate only and, thus, is
free of any biological additives. Sugars including maltose, lactose, sucrose and
dextran may also be added as may be NaCl and methionine. In liquid preparations
buffer systems may be used to reduce the pH value to stabilise the solution. Reduced
pH values, however, are increasing injection site pain (Dressler et al. 2016a).

Manufacturing The manufacturing of BT drugs is a complex and closely con-

trolled process as it directly influences core features of the final drug.

Manufacturing differs with respect of production continuity. BT drugs may be

produced by aliquotation of a single masterbatch licensed by the registration
authorities. They may also be produced by a controlled and licensed continuous
production process generating batches continuously. Originally, Botox® was based
on the masterbatch 79/11 acquired from the Alan Scott’s Oculinum Company. 1998
the manufacturing process was changed to a continuous one to increase SBA and to
reduce antigenicity (Jankovic et al. 2003). All major BT drugs are now manufactured
continuously. Purification of the bacterial broth is an important manufacturing
process. It should generate high drug purity together with low degree of BNT
degradation. BNT activation (‘knicking’) should yield a high degree of activated
BNT. The specific biological activity (SBA), i.e. the potency per total BNT content,
was introduced some time ago as a parameter to predict the antigenicity of BT drugs
(Dressler and Hallett 2006). A low SBA indicates high risks for BT antibody
formation. Low SBA may be the product of suboptimal purification and incomplete
knicking causing SBA differences between BT drugs of the same BT type. SBA may
also be different amongst different BT types. BT-A has the highest SBA, and BT-B
has a particularly low one. Whether, in the case of the only available BT-B drug
Myobloc®, the low SBA is a general property of BT-B or whether it reflects its
particular manufacturing remains open. Repeated potency testing during the
manufacturing process of BT drugs was based on animal testing sacrificing large
numbers of mice. State of the art potency testing is now performed by cell-based
assays. Although Allergan, Ipsen and Merz are applying this technique, still a large
percentage of their BT drugs have to be produced with conventional animal potency
tests as many registration authorities are not yet prepared to accept cell-based assays.
In the future entry of new BT drugs to the North American and European markets
will most likely only be granted when the manufacturing uses cell-based assays.
Optimal manufacturing excels with a high inter-batch potency consistency.
Stabilisation of BT drugs may be achieved by various processes including
lyophilisation (freeze drying), vacuum drying and pH reduction. Potency stability
of the BT drug is an important feature as it affects logistics (temperature control,
shelf life) as well as economics of use (Dressler and Bigalke 2017b). Potency
labelling should be directly comparable between BT drugs.
 D. Dressler

Manufacturer’s Support The BT drug itself should be backed up by a reliable

manufacturer providing sufficient product documentation, product support, reliabil-
ity of drug supply, counterfeit protection, handling safety by differentiability of vials
with different potencies (Dressler and Adib Saberi 2017b) and reasonable denomi-
nation of packaging size (potency per vial, packages per overpack) and – last but not
least – a competitive pricing per adjusted mouse unit.

Botulinum Toxin Drugs BT drugs have unique features: they are not patentable as
such, they have an enormous spectrum of indications, their therapeutic doses range
spread with a factor of 1,000, they represent a completely new therapeutic principle,
they require highly individualised injection schemes developed by trained injectors
and they have remarkably long commercial life cycles. This profile demonstrates the
enormous therapeutic potential, but, at the same time, generates numerous
challenges including qualitative and quantitative off-label use and the necessity to
offer user training and to prevent therapy failure due to suboptimal application
techniques. Therapeutic BT preparations currently available or under development
are shown in Table 2.

In 1989 the US drug Botox® (onabotulinumtoxinA) was the worldwide first BT

drug registered. In 1991 came the UK drug Dysport® (abobotulinumtoxinA), in
2000 another US drug Myobloc® (rimabotulinumtoxinB) and in 2005 the German
drug Xeomin® (incobotulinumtoxinA). These drugs and their aesthetic analogues
are currently the only BT drugs available in North America and Europe. In 1997
Hengli was first registered in the People’s Republic of China, but, so far, has not
reached core foreign markets. In the meantime, many other BT drugs are being
developed in the USA, the Republic of Korea, the Russian Federation, the UK, Iran
and India. Table 2 gives an overview. Most of these drugs are commercially
targeting aesthetic uses in fringe markets, but also therapeutic registrations in
North America and Europe are being prepared. The most active BT drug develop-
ment place is currently the Republic of Korea with companies including Medytox,
Daewoong and Hugel.

Further Development There are several directions of further BT drug develop-

ment. Firstly, all companies are continuously trying to expand the indication spec-
trum of their BT drugs and to search for novel indications. Whether the
antidepressive effects described will, indeed, establish a new class of action of BT
drugs remains unclear. Also unclear is the perspective of developing potential anti-
inflammatory effects. Some companies are trying to prolong or to reduce BT’s
duration of action. Whilst prolonging the duration of action may provide some
benefit for patients, it is hard to imagine indications for BT drugs with reduced
duration of action. Most advanced is a project by Revance of the USA to prolong
BT’s duration of action by co-administration of a proprietary protein. So far, proof of
concept is still lacking and potential risks to the motoneuron pool by long-term
exposure to a foreign protein have not been sufficiently addressed. Another devel-
opment goal are liquid preparations of existing BT drugs. Most advanced is Ipsen.
Clinical Pharmacology of Botulinum Toxin Drugs

Table 2 Therapeutic botulinum toxin preparations

Manufacturers and partners
Generic name Trade name (past and present) Country Specifics
OnabotulinumtoxinA Botox Allergan-AbbVie USA/ BT-A
Botox® Ireland
Cosmetics®
Vistabel®
AbobotulinumtoxinA Dysport® Ipsen/Medicis UK/France/ BT-A
Azzalure® USA
Reloxin®
IncobotulinumtoxinA Xeomin® Merz Pharmaceuticals Germany BT-A, no complexing
Xeomin proteins
Cosmetics®
Bocouture®
RimabotulinumtoxinB NeuroBloc® US WorldMeds/Eisai/ USA BT-B, liquid preparation
Myobloc® Sloan/Elan/Solstice
NerBloc®
LanbotulinumtoxinA Hengli® Lanzhou Institute of P.R. China BT-A, Botox® analogon
Lantox® Biological Products/Hugh
Lanzox® Source
CBTX-A®
Prosigne®
Redux®
Liftox®
Dituroxal®
Neuronox® Medytox R. Korea BT-A, Botox® analogon
Meditoxin®
Botulift®
Cunox®
Coretox® Medytox R. Korea BT-A, Xeomin®
analogon,
no complexing proteins,
no biological excipients
Innotox® Medytox/Allergan R. Korea/ BT-A, liquid preparation
USA
Botulax® Hugel R. Korea
Zentox®
Regenox®
PrabotulinumtoxinA Nabota® Daewoong/Evolus- R. Korea/ BT-A, Botox® analogon
Jeuveau® Alphaeon USA
Evosyal®
DaxibotulinumtoxinA RTT150 Revance USA BT-A, protein additive
Revance/Mylan USA/ BT-A, Botox® analogon,
Netherlands biosimilar approach
Relatox® Microgen Russia BT-A, Botox® analogon
Botulax® Hugel R. Korea BT-A, Botox® analogon
Masport® Masoundarou I.R. Iran BT-A, Dysport®
analogon
CosmeTox® Transdermal USA BT-A, cream
BTXA® Intas India BT-A, Botox® analogon
Botogenie BioMed India BT-A, Botox® analogon
EB-001 Bonti/Allergan USA BT-E
MCL005 Malvern Cosmeceuticals UK BT-A, topic gel
ANT-1207 Anterios/Allergan USA BT-A, lotion
 D. Dressler

However, the registration process seems to falter, probably due to potency

differences between both Dysport® preparations. Another liquid preparation is
Innotox® provided by Medytox. In the future, most new BT drugs will be second-
generation BT drugs lacking CP. Several companies are trying to develop BT drugs
without biological excipients to reduce the potential risk of HIV or BSE transmis-
sion. Medytoxin’s Innotox® is the first of this kind of BT drugs. Mainly for aesthetic
indications, transdermal BT application avoiding injection site pain seems attractive.
Revance apparently has stopped their project using their proprietary protein for this
purpose. All new BT drugs should have improved antigenicity to advance the
potential of BT therapy. High antigenicity, unexpected by lack of SBA calculations
and undetected by insufficient registration trials, may lead to failure of the drug in the
market as seen with the registration of Myobloc®. Trying to provide data to apply for
drug registration based on a biosimilarity approach is challenging, but may have
huge potential marketing implications. Most new BT drugs, however, are based on a
business model using mainly Botox® analogons and trying to get a market share by
price reduction.

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