Abstract
Botulinum neurotoxin type A (BTX-A) weakens voluntary muscle strength and is an effective therapy for focal dystonia, including cervical dystonia (CD) and benign essential blepharospasm (BEB). It is also known to relieve hemifacial spasm and focal spasticity in children and adults. In addition, BTX-A has been shown to be effective in a wide range of other indications, such as gastrointestinal disorders, hyperhidrosis and cosmetic wrinkle correction (e.g. glabellar frown lines). A new formulation of BTX-A, NT 201 (XEOMIN®) has been developed. NT 201 is a formulation of pure BTX-A free of complexing proteins and, therefore, may have a reduced immunogenic potential compared with other BTX-A preparations. The pre-clinical and clinical development of NT 201 is reviewed in this article.
A total of five clinical trials were completed in Europe and Israel. Two studies were conducted in 46 healthy volunteers. A further three studies in 816 patients were conducted to provide data on the safety and efficacy of NT 201 in the treatment of CD and BEB. NT 201 was found to provide non-inferior efficacy and safety profiles in the treatment of CD and BEB compared with a BTX-A preparation containing complexing proteins (BOT [BOTOX®]). The clinical development programme of NT 201 showed a 1 : 1 NT 201 to BOT dose ratio. The pre-clinical studies conducted with NT 201 showed an acceptable safety profile and support the use of NT 201 in an intramuscular administration regimen for patients with CD and BEB. NT 201 was effective, well tolerated and non-inferior to BOT in the treatment of both CD and BEB. In addition, there were no differences between the two therapies in terms of onset of action, duration and waning of effect. Further research is required to determine the long-term efficacy and safety profile of NT 201.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database Syst Rev 2005; (1): CD003633
Costa J, Espirito-Santo C, Borges A, et al. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev 2004; (2): CD004900
Tsui JK, Bhatt M, Calne S, et al. Botulinum toxin in the treatment of writer’s cramp: a double-blind study. Neurology 1993; 43 (1): 183–5
Mall V, Heinen F, Siebel A, et al. Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study. Dev Med Child Neurol 2006 Jan; 48 (1): 10–3
Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl Med J 2002 Aug; 347 (6): 395–400
Brisinda G, Maria G, Bentivoglio AR, et al. The role of botulinum toxin in gastrointestinal disorders. In: Brin MF, Hallett M, Jankovic J, editors. Scientific and therapeutic aspects of Botulinum toxin. Philadelphia (PA): Lippincott Williams & Wilkins, 2002: 269–85
Naumann M. Evidence-based medicine: botulinum toxin in focal hyperhidrosis. J Neurol 2001 Apr; 248 (1): 131–3
Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg 2004 Nov; 114 (6): 1–22
Cather JC, Menter A. Update on botulinum toxin for facial aesthetics. Dermatol Clin 2002 Oct; 20 (4): 749–61
Butler AG, Duffey PO, Hawthorne MR, et al. An epidemiologic survey of dystonia within the entire population of northeast England over the past nine years. Adv Neurol 2004; 94: 95–9
Jankovic J. Treatment of cervical dystonia with botulinum toxin. Mov Disord 2004 Mar; 19 (8): S109–15
King Ching Tsui J. Blepharospasm and hemifacial spasm. In: Brin MF, Comella C, Jankovic J, editors. Dystonia: etiology, clinical features, and treatment. Philadelphia (PA): Lippincott Willimas & Wilkins, 2004: 151–7
Berardelli A, Kaji R, Currà A. Physiology of dystonia. In: Brin MF, Comella C, Jankovic J, editors. Dystonia: etiology, clinical features, and treatment. Philadelphia (PA): Lippincott Williams & Wilkins, 2004: 33–7
Hallett M. Blepharospasm: recent advances. Neurology 2002 Nov; 59 (9): 1306–12
Kessler KR, Benecke R. Botulinum toxin: from poison to remedy. Neurotoxicology 1997; 18 (3): 761–70
De Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A 1999 Mar; 96 (6): 3200–5
Lee JC, Yokota K, Arimitsu H, et al. Production of antineurotoxin antibody is enhanced by two subcomponents, HA1 and HA3b, of Clostridium botulinum type B 16S toxinhaemagglutinin. Microbiology 2005 Nov; 151 (Pt 11): 3739–47
Blümel J, Frevert J, Schwaier A. Comparative antigenicity of three preparations of botulinum neurotoxin type A in the rabbit [abstract]. Neurotox Res 2006; 9 (2): 238
Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology 2003 Apr; 60 (7): 1186–8
Jost WH, Kohl A, Brinkmann S, et al. Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT201) compared with commercially available botulinum toxin type A (BOTOX®) in healthy volunteers. J Neural Transm 2005; 112 (7): 905–13
Wohlfarth K, Mueller C. Safety, efficacy, and duration of effect of a new botulinum neurotoxin type A preparation free of complexing proteins [abstract]. Mov Disord 2005; 20 (10): S11
Wohlfarth K, Müller C, Sassin I, et al. No spread of a new botulinum neurotoxin type A preparation in adjacent muscles. Neurotox Res 2006; 9 (2): 236
Benecke R, Jost W, Kanovsky P, et al. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005; 64: 1949–51
Roggenkämper P, Jost WH, Bihari K, et al. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm. J Neural Transm 2006 Mar; 113 (3): 303–12
Merz Pharmaceuticals GmbH. Summary of product characteristics Xeomin®. Frankfurt: Merz Pharmaceuticals GmbH, 2006 Mar
Schantz EJ, Kautter DA. Microbiological methods: standardized assay for Clostridium botulinum neurotoxins. J Assoc Off Anal Chem 1978; 61 (1): 96–9
Merz Pharmaceuticals GmbH. Oral toxicity of NT-101 in CD-1 mice. Frankfurt: Merz Pharmaceuticals GmbH, 2000. LPT Report No. 12798/99, study report
Fujinaga Y, Inoue K, Nomura T, et al. Identification and characterization of functional subunits of Clostridium botulinum type A progenitor neurotoxin involved in binding to intestinal microvilli and erythrocytes. FEBS Lett 2000 Feb; 467 (2–3): 179–83
Sharma SK, Singh BR. Hemagglutinin binding mediated protection of botulinum neurotoxin from proteolysis. J Nat Neurotoxins 1998; 7 (3): 239–53
Merz Pharmaceuticals GmbH. Comparative systemic toxicity of NT-201 in mice following intravenous administration. Frankfurt: Merz Pharmaceuticals GmbH, 1998. LPT Report No. 11252/1/98 + Addendum, study report
Merz Pharmaceuticals GmbH. NT 201–13 week toxicity study with repeated intramuscular administrations in the cynomolgus monkey. Frankfurt: Merz Pharmaceuticals GmbH, 2004. Study Number 442/016, study report
Milano S, Chalencon E, Lege P, et al. Telemetry as a tool to evaluate simultaneously the efficacy and safety of a neuromuscular blocking agent in the monkey [abstract]. J Pharmacol Toxicol Methods 2005; 52 (1): 202
Göschel H, Wohlfarth K, Frevert J, et al. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies — therapeutic consequences. Exp Neurol 1997; 147 (1): 96–102
Buchman AS, Comella CL, Stebbins GT, et al. Determining a dose-effect curve for botulinum toxin in the sternocleidomastoid muscle in cervical dystonia. Clin Neuropharmacol 1994; 17 (2): 188–95
Consky ES, Lang AE. Clinical assessments of patients with cervical dystonia. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker, 1994: 211–37
Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology 1987; 37 (4): 616–23
Goertelmeyer R, Brinkmann S, Comes G, et al. The Blepharospasm Disability Index (BSDI) for the assessment of functional health in focal dystonia. Clin Neurophysiol 2002; 113 (1): S77–8
Görtelmeyer R, Grafe S, Comes G. The Blepharospasm Disability Index (BSDI): reliability and validity. Neurotox Res 2006; 9 (2): 237
Epidemiologic Study of Dystonia in Europe. Sex-related influences on the frequency and age of onset of primary dystonia. Neurology 1999 Nov; 53 (8): 1871–3
Anderson RL, Patel BC, Holds JB, et al. Blepharospasm: past, present, and future. Ophthal Plast Reconstr Surg 1998 Sep; 14 (5): 305–17
Santos JI, Swensen P, Glasgow LA. Potentiation of Clostridium botulinum toxin aminoglycoside antibiotics: clinical and laboratory observations. Pediatrics 1981; 68 (1): 50–4
Wang YC, Burr DH, Korthals GJ, et al. Acute toxicity of aminoglycoside antibiotics as an aid in detecting botulism. Appl Environ Microbiol 1984 Nov; 48 (5): 951–5
Yamada S, Kuno Y, Iwanaga H. Effects of aminoglycoside antibiotics on the neuromuscular junction: part I. Int J Clin Pharmacol Ther Toxicol 1986; 24 (3): 130–8
Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol 2000 Aug; 43 (2): 249–59
Simpson LL. The interaction between aminoquinolines and presynaptically acting neurotoxins. J Pharmacol Exp Ther 1982 Jul; 222 (1): 43–8
Walts LF. Neuromuscular blocking drugs. Otolaryngol Clin North Am 1981 Aug; 14 (3): 501–13
Brashear A, Watts MW, Marchetti A, et al. Duration of effect of botulinum toxin type A in adult patients with cervical dystonia: a retrospective chart review. Clin Ther 2000 Dec; 22 (12): 1516–24
Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 2005 Nov; 65 (9): 1423–9
Defazio G, Livrea P. Primary blepharospasm: diagnosis and management. Drugs 2004; 64 (3): 237–44
Jankovic J. Treatment of cervical dystonia. In: Brin MF, Comella C, Jankovic J, editors. Dystonia: etiology, clinical features, and treatment. Philadelphia (PA): Lippincott Williams & Wilkins, 2004: 159–66
Jankovic J. Botulinum toxin therapy for cervical dystonia. Neurotox Res 2006; 9 (2): 145–8
Borodic G, Johnson E, Goodnough M, et al. Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology 1996; 46 (1): 26–9
Acknowledgements
The authors would like to thank Georg Comes for excellent biometrical advice. Drs Blümel and Grafe are full time employees of Merz Pharmaceuticals which sponsored all the studies discussed in this manuscript and is the Market Authorization Holder for NT 201 in Germany.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jost, W.H., Blümel, J. & Grafe, S. Botulinum Neurotoxin Type A Free of Complexing Proteins (XEOMIN®) in Focal Dystonia. Drugs 67, 669–683 (2007). https://doi.org/10.2165/00003495-200767050-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200767050-00003