Drugs

, Volume 62, Issue 4, pp 705–722

Botulinum Toxin B

A Review of its Therapeutic Potential in the Management of Cervical Dystonia
Adis Drug Evaluation

Summary

Abstract

Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles.

Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient-assessed pain and patient-/physician-assessed global improvement ratings.

In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a ≥20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%).

Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events.

Conclusions: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.

Pharmacodynamic Properties

Botulinum neurotoxins are synthesised by Clostridium botulinum as single-chain polypeptides of approximately 150kD; they have limited toxicity until they are cleaved by bacterial proteases into light (≈50kD) and heavy (≈100kD) chains that are linked by a disulphide bond. As a single-chain polypeptide (150kD), botulinum neurotoxin B consists of 1290 amino acids; endopeptidase cleavage occurs between lysine 440 and alanine 441, resulting in two polypeptide chains linked by a disulphide bond between cysteine residues 436 and 445. Botulinum toxins consist of noncovalent multiprotein complexes that contain additional non-neurotoxic proteins.

When injected into dystonic muscles, botulinum toxins produce muscle weakness through inhibition of acetylcholine release from neuromuscular junctions. The heavy chain of botulinum neurotoxin B binds specifically to synaptotagmin II on the presynaptic membrane surface by associating with gangliosides GT1b or GD1a to form a receptor complex. In the presence of ganglioside GT1b 5ng, maximum binding capacity (Bmax) for botulinum neurotoxin B was 3.88 nmol/mg protein in an in vitro model; at a concentration of ganglioside GT1b 0.31ng, Bmax reduced to 0.67 nmol/mg protein.

After internalisation of the neurotoxin, the light chain, acting as a zinc endopeptidase, diminishes acetylcholine release by proteolytically cleaving one or more soluble or membrane-bound protein components of the SNARE [soluble N-ethylmaleimide sensitive factor attachment protein (SNAP) receptor] complex. Botulinum neurotoxin B catalyses proteolytic cleavage of the vesicle-associated membrane protein synaptobrevin (an integral membrane protein of small synaptic vesicles that is essential for acetylcholine exocytosis). In contrast to the action of botulinum neurotoxin B, botulinum neurotoxin A cleaves SNAP-25 (25kD synaptosomal-associated protein).

Compared with botulinum toxin A, botulinum toxin B exhibited less spread of paralytic activity to noninjected nearby (first dorsal interosseous) and relatively distant (abductor digiti minimi) muscles in a primate hand model, at doses of the two toxins that produced a similar effect in injected abductor pollicis brevis muscles.

Botulinum neurotoxins A and B are antigenically distinct and, therefore, do not serologically cross-react. In contrast, some of the non-neurotoxic proteins that are associated with type A and B neurotoxins do cross-react. Although the clinical significance of the development of antibodies to botulinum toxin B has not been determined, in vitro and in vivo assays have indicated the presence of antibodies and serum neutralising activity after repeated administration of botulinum toxin B.

Clinical Efficacy

Early-phase trials indicated that doses of botulinum toxin B up to 12 000U were effective and generally well tolerated in patients with cervical dystonia. Subsequently, data from three double-blind, randomised, placebo-controlled trials have confirmed that a single intramuscular dose of botulinum toxin B 2500 to 10 000U, divided among affected muscles, effectively reduces the severity, disability and pain of cervical dystonia. Efficacy was evaluated using the validated Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), consisting of the sum of three subscale scores that include severity, disability and pain. Visual analogue scales, including the Patient Analogue Pain Assessment and Patient’s and Physician’s Global Assessment of Change, were also used to measure subjective improvements in overall functioning and pain.

In two of the trials (in patients with either botulinum toxin A-responsive or -resistant disease), botulinum toxin B10 000U reduced mean TWSTRS-Total scores at week 4 (primary efficacy measure) by 11.7 (25%) or 11 (21 %) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. The median time taken for TWSTRS-Total score to return to baseline (estimated by Kaplan-Meier analysis) was 16 weeks for botulinum toxin B 5000 or 10 000U and 8 or 9 weeks for placebo (p ≤ 0.008 for botulinum toxin B vs placebo). At week 4, Patient Analogue Pain Assessment scores and Patient’s and Physician’s Global Assessment of Change scores were all significantly improved in botulinum toxin B 5000 or 10 000U recipients compared with placebo recipients.

Mean absolute reductions from baseline in TWSTRS-Total score at week 4 in the other placebo-controlled trial (in a mixed population of patients with botulinum toxin A-responsive and -resistant disease) were 11.6, 12.5 and 16.4 after botulinum toxin B 2500, 5000 and 10 000U, respectively (baseline values not reported), compared with a mean reduction of 3.3 in placebo recipients (p < 0.05 for all comparisons). In addition, the percentage of patients showing a clinical response (an improvement in TWSTRS-Total score from baseline to week 4 of at least 20%) was significantly higher at all three doses of botulinum toxin B (58 to 77%) compared with placebo (27%). Response rates based on TWSTRS sub-scale scores at week 4 for botulinum toxin B 10 000U were also significantly greater than those for placebo recipients (67 vs 20%, 50 vs 23% and 83 vs 40% for TWSTRS-Disability, -Severity and -Pain subscales, respectively).

Tolerability

Botulinum toxin B is generally well tolerated. Treatment-related adverse events were mostly mild or moderate, with the most frequently reported adverse events in botulinum toxin B recipients being dry mouth (24 to 44% of patients) and dysphagia (22 to 28%). No serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. In a randomised, double-blind, placebo-controlled study in which patients with botulinum toxin A-responsive cervical dystonia received botulinum toxin B 5000 or 10 000U, adverse events were more common in the higher botulinum toxin B dosage group than in the other two treatment groups.

Dosage and Administration

Botulinum toxin B is indicated for the treatment of cervical dystonia. In the US, botulinum toxin B 2500 to 5000U, divided among affected muscles, is the recommended initial dose in patients with a prior history of tolerating botulinum toxin injections. Patients with no prior history of tolerating botulinum toxin injections should receive a lower initial dose. The recommended adult starting dose in the UK is 5000 to 10 000U, divided between the two to four most affected muscles. Dose and frequency of administration should be adjusted for each individual patient depending on clinical response.

In the absence of published data regarding the use of botulinum toxin B during pregnancy, the drug should only be used if clearly needed (according to US prescribing information); in the UK, botulinum toxin B is contraindicated in pregnant or lactating women.

Botulinum toxin B is supplied as a refrigerated, ready-to-use, sterile solution, buffered to pH 5.6, in vials containing 2500, 5000 or 10 000U.

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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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