Basic science: Xeomin - Clinical Tree

Summary and key features

IncobotulinumtoxinA (NT 201, Xeomin™, Bocouture ™) is an effective and well-tolerated treatment for facial wrinkles that is approved for the treatment of glabellar frown lines, lateral periorbital lines (crow’s feet) and upper facial lines in many countries.
IncobotulinumtoxinA does not contain complexing proteins and other impurities that are found in other commercially available botulinum toxin type A products.
Complexing proteins have no therapeutic effect, do not prevent the active neurotoxin from diffusing and may increase the risk of antibody formation.
IncobotulinumtoxinA is highly stable and can be stored at room temperature.
IncobotulinumtoxinA has a higher specific biological activity than other available botulinum toxin type A preparations, such as onabotulinumtoxinA (Botox/Vistabel) and abobotulinumtoxinA (Dysport/Azzalure).
In practice, the clinical equipotency of incobotulinumtoxinA and onabotulinumtoxinA has been proven when a dose ratio of 1:1 is used. Multiple small dose injections result in a precise and predictable outcome.
The best results are achieved when the face is treated as a whole, since treating some muscles or areas in isolation may draw attention to untreated areas.

Introduction

Botulinum toxins have been used aesthetically since 1987(35 years) and are an effective treatment for facial wrinkles. According to the cosmetic surgery national data bank statistics of the American Society for Aesthetic Plastic Surgery (found at www.surgery.org ), botulinum toxin treatment was the most common non-surgical aesthetic procedure performed in the USA in 2021.

IncobotulinumtoxinA (NT 201/Xeomin, Bocouture) is manufactured by Merz Pharmaceuticals GmbH (Frankfurt am Main, Germany). It is used to treat certain neurological conditions (e.g., cervical dystonia, blepharospasm, post-stroke upper limb spasticity, and sialorrhea) and has a number of uses in the field of aesthetic medicine. IncobotulinumtoxinA is licensed in Europe under the trade name Bocouture for the treatment of moderate to severe glabellar frown lines (GFL), lateral periorbital lines (LPL, crow’s feet), and moderate to severe horizontal forehead lines (HFL) seen at maximum contraction in adults younger than 65 years when the severity of these lines has an important psychological impact for the patient. The licensed indications for Bocouture use vary and are specific for each country. In the USA, incobotulinumtoxinA is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe GFL, upper limb spasticity, blepharospasm, cervical dystonia, and sialorrhea under the trade name Xeomin. Because it contains only the 150 kDa protein responsible for the therapeutic effect, incobotulinumtoxinA differs from the other botulinum toxin type A products on the market (onabotulinumtoxinA, Botox/Vistabel, Allergan, Irvine, CA, USA; abobotulinumtoxinA, Dysport/Azzalure, Ipsen Ltd, Paris, France), which contain other clostridial proteins (complexing proteins, also known as neurotoxin-associated proteins) ( Table 5.1 ).

TABLE 5.1

Botulinum Toxin Type A Product Comparison

Derived from Azzalure®. (2015). Summary of product characteristics . Berkshire, UK: Ipsen Ltd; Bocouture®. (2016). Summary of product characteristics. Germany: Merz Pharmaceuticals GmbH; Vistabel®. (2015). Summary of product characteristics. Irvine, CA: Allergan Inc.

	OnabotulinumtoxinA	AbobotulinumtoxinA	IncobotulinumtoxinA
Units per vial	50 U	125 U	50 U
Clostridial strain	Hall	Hall	Hall
Clostridial strain	Type A	Type A	Type A
Molecular composition	150 kDa neurotoxin and complexing proteins	150 kDa neurotoxin and complexing proteins	150 kDa neurotoxin
Recommended dose for treatment of glabellar lines in LD50 units	20 U	50 U	20 U
Excipients	HSA	HSA	HSA
Excipients	Sodium chloride	Lactose monohydrate	Sucrose

HSA, Human serum albumin.

Properties of incobotulinumtoxinA

Purity

The therapeutically active substance in all botulinum toxin products is the neurotoxin with a molecular weight of 150 kDa produced by the bacterium Clostridium botulinum type A. The clostridia incorporate the neurotoxin in large complexes with several other proteins, the complexing proteins. During the manufacture of incobotulinumtoxinA, following fermentation of C. botulinum type A and extraction of the toxin, the complexing proteins are removed by chromatography. IncobotulinumtoxinA therefore contains markedly less clostridial proteins than onabotulinumtoxinA and abobotulinumtoxinA ( Fig. 5.1 ). Further, in contrast to onabotulinumtoxinA, incobotulinumtoxinA is free of deoxyribonucleic acid (DNA). Using a high-sensitivity sandwich ELISA, Frevert measured the amounts of neurotoxin per 100 U of onabotulinumtoxinA, incobotulinumtoxinA and abobotulinumtoxinA, reporting values of 0.73 ng, 0.44 ng, and 0.65 ng, respectively. The specific biological activity per mass of neurotoxin protein (U/ng neurotoxin) was then calculated, giving incobotulinumtoxinA the highest specific biological activity at 227 U/ng compared with 137 U/ng for onabotulinumtoxinA and 154 U/ng for abobotulinumtoxinA (although it should be noted that the units of abobotulinumtoxinA are different from those of onabotulinumtoxinA and incobotulinumtoxinA). This suggests that, in addition to containing complexing proteins, onabotulinumtoxinA may also contain denatured/inactivated neurotoxin, unlike incobotulinumtoxinA (see Fig. 5.1 ).

Fig. 5.1, The amount of clostridial protein and neurotoxin protein contained in incobotulinumtoxinA, onabotulinumtoxinA and abobotulinumtoxinA per dose approved for the treatment of glabellar frown lines.

Stability

IncobotulinumtoxinA can be stored at room temperature and without refrigeration for 4 years. In addition to the practical advantage of not requiring cold storage, incobotulinumtoxinA did not lose activity in a temperature stress stability study and its quality did not decrease following storage at 60°C for 1 month. Further evidence for the stability of incobotulinumtoxinA has been provided by a split-face study that involved injection of 10 U into the LPL of 21 subjects and found no difference in the efficacy or longevity of freshly reconstituted product compared with product that had been reconstituted and stored for 1 week at 25°C. However, in accordance with the prescribing information, once reconstituted, incobotulinumtoxinA should be stored at 2°C to 8°C and used within 24 hours to limit the risk of bacterial growth.

Pearl 1:

The high stability of incobotulinumtoxinA allows it to be stored at room temperature before reconstitution.

Diffusion

Under acidic conditions, the complexing proteins form a high-molecular-weight complex (900 kDa) with the neurotoxin. Accordingly, it was speculated that complexing proteins might limit the diffusion of active neurotoxin within the target muscle; however, experiments on animals and humans suggest otherwise. The diffusion of onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA using a 1:4:1 dose conversion ratio was investigated in a mouse model using staining for neural cell adhesion molecule (N-CAM) as a marker. Because N-CAM is expressed only by denervated muscle cells, it is suitable for testing for muscles affected by botulinum toxin type A. Following injection into the tibialis anterior (TA) muscle of the mouse leg, there was limited diffusion into tissue that was adjacent to the site of injection and no difference in diffusion between the three toxins. A clinical study showed no difference in the size of the anhidrotic area produced following injection of 5 U of incobotulinumtoxinA (free from complexing proteins) compared with 5 U of onabotulinumtoxinA (containing complexing proteins) on either side of the forehead after 6 weeks and 6 months.

These results suggest that complexing proteins have no effect on spread. Eisele and co-workers showed that reconstitution of onabotulinumtoxinA and abobotulinumtoxinA at physiological pH leads to complete dissociation of the 900 kDa complexes and results in at least 85% of the neurotoxin in its free form, with more than 80% of the 150 kDa neurotoxin released from complexes in less than 1 minute at physiological pH. Therefore, the presence or absence of complexing proteins in the original preparation is irrelevant in terms of diffusion.

Pearl 2:

Complexing proteins are unnecessary; they have no function in limiting the diffusion of the neurotoxin and do not contribute to the therapeutic effect. IncobotulinumtoxinA, with its 150 kDa neurotoxin, is effective without any other clostridial proteins.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here