Comparison of botulinum toxins

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9 Comparison of botulinum toxins

Summary and Key Features

Botox® (onabotulinumtoxinA), Dysport® (abobotulinumtoxinA) and Xeomin® (incobotulinumtoxinA) are the three commercially available formulations of BoNT-A existing in the US today

All three formulations are FDA approved for the treatment of glabellar lines; in addition, all are highly effective in treatment of dynamic rhytides of the face and neck

The botulinum neurotoxin molecule is a single-chain polypeptide found in its native state surrounded by varying amounts of complexing proteins; Botox® contains a larger number of complexing proteins than Dysport®; Xeomin® does not contain complexing proteins

Although the exact dosing ratio is unclear and may vary depending on application, the ratio between Botox® : Dysport® : Xeomin® is likely to be around 1 : 2.5 : 1

Clinically the duration of action appears to be similar for all currently available BoNT-A preparations; however, further investigation is needed

Some evidence suggests that the degree of diffusion may vary between formulations when used to treat hyperhidrosis; however, these differences, if any, are subtle

Therapeutic failure of BoNT-A in cosmetic use is very rare and the role of blocking antibodies remains unclear

The safety of Botox® and Dysport® has been well established and Xeomin®, while a newer product, appears to have a similar safety profile

Vials of Botox® and Dysport® must be kept refrigerated prior to reconstitution; however, Xeomin® may be stored at room temperature prior to use

Introduction

Botulinum toxin is a naturally occurring protein produced by the anaerobic bacterium Clostridium botulinum. The protein acts as a neurotoxin by blocking the release of acetylcholine at the neuromuscular junction of striated muscle, thereby blocking neuromuscular motor transmission. This unique property has been found to have great clinical utility, treating such diverse medical conditions as blepharospasm, hyperhidrosis, and dynamic rhytides.

Seven serologically distinct types of botulinum toxin have been identified – designated as types A, B, C1, D, E, F, and G. Only botulinum toxin A and B are used clinically, with serotype A being the most potent. At this time, rimabotulinumtoxinB or Myobloc® (Solstice Neurosciences, Inc; South San Francisco, CA) is the only commercially available botulinum toxin B. Initially approved by the FDA in 2000 for the treatment of cervical dystonia, its use in cosmetic applications has been limited by systemic anticholinergic adverse effects and high antigenicity. Therefore the following discussion will focus solely on botulinum toxin A (BoNT-A).

BoNT-A, like all the botulinum toxin serotypes, causes flaccid muscle paralysis by blocking acetylcholine release at neuromuscular junctions. The compound, first purified in 1946 by Dr Edward Shantz, was first found to have a cosmetic application in 1988 when Drs Jean and Alastair Carruthers observed improvement in the appearance of periorbital rhytides in patients treated for blepharospasm. In 1992, the Carruthers published their first study describing its cosmetic use in the treatment of glabellar frown lines. Subsequent randomized controlled studies provided evidence for its safety and efficacy leading to FDA approval of BoNT-A for cosmetic procedures in 2003. Today BoNT-A is considered a vital component of non-invasive facial rejuvenation and is the most common non-surgical cosmetic procedure performed.

Types of botulinum toxin A

There are multiple formulations of BoNT-A available in the US and internationally; however, the practitioner must be aware that these products are not interchangeable and important differences exist. As such, in 2009 the US FDA established unique drug names to ‘help ensure patient safety and reduce confusion’ (Table 9.1). What follows is a review of available products and their known and theoretical differences.

There are currently three formulations of BoNT-A available in the US today for cosmetic applications: onabotulinumtoxinA or Botox® (Allergan, Inc, Irvine, California, USA), abobotulinumtoxinA or Dysport® (Ipsen Biofarm Ltd, Berkshire, UK) and incobotulinumtoxinA or Xeomin®® (Merz Pharmaceuticals, Frankfurt am Main, Germany). For ease of discussion, the products will be referenced by their trade names moving forward. Botox® (Fig. 9.1) was the first to become available and continues to dominate the worldwide cosmetic market. In the USA it is approved for the treatment of glabellar lines and hyperhidrosis. It has also been shown to be highly effective for such ‘off-label’ uses as the treatment of dynamic rhytides of the forehead, periorbital area, midface, perioral area, and neck.

Dysport® (Fig. 9.2), another preparation of BoNT-A, is approved for the treatment of glabellar lines. It has become increasingly popular worldwide since its introduction and has been shown to have similar cosmetic applications to Botox®.

A third product, Xeomin® (Merz Pharmaceuticals, Frankfurt am Main, Germany) was previously indicated only for treatment of cervical dystonia and blepharospasm. However, as of July 2011, it also gained FDA approval for the treatment of glabellar rhytides. Xeomin® has become available in the United States in the spring of 2012.

Other BoNT-A products currently in development include Purtox® (Mentor Corporation, Santa Barbara, California, USA), Neuronox® (Medy-Tox, Chung-cheongbuk-do, Korea), and Prosigne® (Lanzhou, China). Purtox® recently completed the first of three Phase III clinical trials with promising results. Clinical trial data in the United States are still pending on the other BoNT-A formulations, some of which are currently available outside the United States. In the future it will be interesting to see how the addition of other BoNT-A products to the market will affect product pricing and patient access to them.

Compositional differences

The botulinum neurotoxin molecule is a 150 kDa single-chain polypeptide consisting of a 100 kDa heavy chain and a 50 kDa light chain. These chains are held together by a disulfide bond and are associated with a zinc atom (Fig. 9.3). In its native state the 150 kDa toxin is found complexed with large protective proteins. These complexing proteins, which are primarily hemagluttinins, act to protect ingested toxin from degradation within the gastrointestinal tract. In neutral to basic pH environments the BoNT-A complex dissociates into the free 150 kDa neurotoxin and high-molecular-weight hemagglutinin components.

The complexing proteins of the native molecule seem to have evolved as a clever mechanism to protect the toxin when ingested by the host. However, the role that these proteins play, if any, in cutaneous injection of BoNT-A is unclear and remains a subject of debate. It has been argued that the proteins help to stabilize the core toxin or that they may help to enhance activity; however, these hypotheses have not been substantiated.

The three available formulations of BoNT-A vary in the presence, absence, and amount of complexing proteins. Botox® is the largest of the available preparations at 900 kDA (Fig. 9.4) and is associated with the most complexing proteins. Due to the method employed in its production, Dysport® may be associated with a variable number of proteins with a molecular weight ranging from 500 to 900 kDa. Uniquely in the group, Xeomin® is composed only of the 150 kDa neurotoxin, free of any complexing proteins. Purtox® will also be a non-complexed formulation of botulinum toxin A.