Basic science: Myobloc®

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7 Basic science

Myobloc^®

Neil S. Sadick, Nils Krueger

Summary and Key Features

• Myobloc^® is the only botulinum toxin product that is based on serotype B

• Botulinum toxin B (BoNT-B) has its own unique mechanism of action, binds specific serotype receptors, and targets specific intracellular proteins

• Myobloc^® requires no reconstitution before injecting as it is available in a liquid formulation

• Myobloc^® is FDA approved for the treatment of abnormal head position and neck pain that accompanies cervical dystonia in adults

• BoNT-B is an important replacement whenever it comes to immunoresistance in patients treated with BoNT-A

• Myobloc^® has a higher rate of adverse effects and the injection can be more painful compared with other BoNT products

• BoNT-B has a rapid onset of effect (within 48 hours after injection). The duration is limited to a maximum of 10–12 weeks

• BoNT-B affects a larger area around the injection point associated with a smoother clinical effect

• The most common side effects when used for the treatment of facial rhytides are xerostomia and headaches as well as dry eyes and brow ptosis

3D basic science: Myobloc^®

Myobloc^® (Solstice Neurosciences, San Francisco, CA), or Neurobloc^® in Europe (Eisai Europe, Hatfield, UK), is the only commercially available drug based on botulinum toxin serotype B (BoNT-B) and was FDA cleared for the treatment of abnormal head position and related pain of cervical dystonia in 2000. Besides this indication, it has been shown to be effective for the treatment of many other diseases like subacromial bursitis, Frey syndrome, spastic trismus, Parkinson disease-related drooling or sialorrhea in children with cerebral palsy. Similar to drugs based on botulinum toxin serotype A (BoNT-A), Myobloc^® has also been used in the field of aesthetic dermatology to treat facial rhytides caused by hyperkinetic muscles and for the management of hyperhidrosis.

Myobloc^® is contributed as a purified solution packaged in ready-to-use vials and requires no reconstitution. The solution is stabilized at pH 5.6 to ensure that the toxin complex is intact with a single-entity molecular weight of approximately 700 kDa. The liquid preparation form enables the toxin to be injected as a uniform and intact complex, as opposed to partially dissociated subunits. The non-lyophilized and non-vacuum-dried preparation also minimizes the amount of denatured protein and secures an active neurotoxin amount of 65%. Myobloc^® is available in vials of 2500, 5000, and 10 000 U, each with a concentration of 5000 U/ml. As the toxic potency depends on several factors and cannot be transferred directly from animals to humans, the equivalency to BoNT-A-based Botox^® / Xeomin^® units is considered to be in a range from 1 : 20 to more than 1 : 125. Myobloc^® can be diluted with saline, as much as sixfold, before injection without loss in total activity and is stable for 9 months when stored at room temperature (25°C) and for >36 months when stored at refrigerated temperatures (2–8°C).

Pharmacology of botulinum toxin B

Botulinum neurotoxins are synthesized as macromolecular complexes of 300–900 kDa and different neurotoxin complex protein structures, depending on the serotype of the clostridial strain that produced it. Every progenitor toxin contains a 150 kDa neurotoxin molecule and one or more non-toxin proteins. At approximately 700 kDa the molecular weight of the BoNT-B complex is in between that of BoNT-A (900 kDa) and all other serotypes, with weights <500 kDa. The neurotoxin complex is composed of associated proteins such as hemagglutinin and a non-toxic, non-hemagglutinin moiety. The active neurotoxin exists in a 150 kDa dichain molecule consisting of a heavy chain of approximately 100 kDA and a light chain of approximately 50 kDA, linked together by a disulfide bond.

Botulinum toxin B affects the nervous system in a similar way to all other botulinum toxins in a series of cellular actions including binding, internalization, and inhibition of acetylcholine release. The heavy chain of the complex contributes to the irreversible binding of the toxin to the serotype-specific protein within the soluble N-ethyl maleimide-sensitive factor attachment protein receptor (SNARE) complex, which is involved in release of acetylcholine-containing vesicles from the presynaptic neuron. The light chain mediates proteolysis of SNARE proteins and subsequent inhibition of synaptic vesicle fusion to the presynaptic membrane of the human motor neurons. This leads to flaccid paralysis associated with botulism. Each serotype cleaves a specific residue on one of the N-ethylmaleimide sensitive factor (NSF) attachment proteins. Botulinum toxin B cleaves the vesicle-associated membrane protein (VAMP) also known as synaptobrevin. VAMP is cleaved by the serotypes F, G, and D too, but at differing locations (Table 7.1). The high specificity of the BoNT light chain cleavage is attributed to the light chain recognizing long SNARE sequences with 30–50 residues indicated by the specific serotype.

Table 7.1 Pharmacology of botulinum toxin serotypes by target / cleavage sizes

Serotype	Target size	Cleaves at
A	SNAP-25*	Gln197–Arg198
B	VAMP†	Glu76–Phe77
C	Syntaxin	Lys253–Ala254
		Lys252–Ala252
	SNAP-25*	Arg198–Ala199
D	VAMP†	Ala67–Asp68
D	VAMP†	Lys59–Leu60
E	SNAP-25*	Arg180–Ile181
F	VAMP†	Gln58–Lys59
G	VAMP†	Ala81–Ala82

^* SNAP-25 is a soluble NSF attachment protein of 25 000 kDa.

^† VAMP = vesicle-associated membrane protein (synaptobrevin).

Immunogenicity

Patients treated with any botulinum toxin can develop neutralizing antibodies that reduce or completely eradicate the toxin’s clinical effectiveness. All botulinum serotypes are antigenically distinct and can cause an individual immune response. The formation of antibodies has been linked to high loads of neurotoxin complex protein. Consequently, botulinum toxin preparations with high specific potencies and low total unit doses have the lowest immunogenicity. The incidence of antibody formation with BoNT-A in cervical dystonia was reported by Berman to be less than 5%. In a study by Jankovic and colleagues, the immunoresistance rate for BoNT-B was found to be up to 30% after 42 months when cervical dystonia patients were treated with high doses of Myobloc^®. Currently there are no published data on immunoresistance in patients treated for aesthetic purposes, but the incidence is considered to be significantly lower as much lower doses are used and the development of antibodies correlates with the total cumulative dose. Patients becoming resistant to one particular serotype can usually be treated with another serotype. As botulinum toxin serotypes share some sequence homology with one another, a theoretical basis for serum cross-reactivity is given, which can further potentiate resistance to other serotypes with multiple injections. Consequential risk factors associated with the evolution of cross-resistant antibodies include treatment of high doses of toxin, increased frequency of administration, and the amount of neurotoxin protein delivered in each injection.

Pearl 1

Resistance to BoNT-A appears more often in the treatment of movement disorders, but can also appear after aesthetic treatments. Myobloc^® may be helpful in people showing resistance to botulinum toxin phenotype A.

Case Study 1

Resistance to BoNT-A

A 38-year-old female presented in the office with a history of treatments with 25 U onabotulinumtoxinA and 75 U abobotulinumtoxinA for upper face rejuvenation. She was unsatisfied because the last treatments had effects for less than 6 weeks.

Due to the apparent BoNT-A resistance, she was switched to BoNT-B. After injection of 2500 U BoNT-B in the upper third of the face, the average duration of effect was 12 weeks.

Myobloc^® in the aesthetics practice

Despite its primary indication in the treatment of cervical dystonia, increasing cosmetic demands for the effective treatment of facial rhytids have provided Myobloc^® with a platform to expand into the dimension of off-label usage. BoNT-B has been successfully investigated for the treatment of hyperkinetic rhytides as well as for the therapy of palmar and axillar hyperhidrosis.

Efficacy in the treatment of hyperkinetic rhytides

BoNT-B is shown to be efficient in the treatment of hyperkinetic rhytides in the upper third of the face. Studies confirm the denervating effect on orbicularis oculi, frontalis, and corrugator supercilii (Table 7.2

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