IncobotulinumtoxinA: A Highly Purified and Precisely Manufactured Botulinum Neurotoxin Type A

January 2019 | Volume 18 | Issue 1 | Original Article | 52 | Copyright © January 2019


Martina Kerscher MD PhD,a Rungsima Wanitphakdeedecha MD MA MSc,b Ada Trindade de Almeida MD,c Corey Maas MD FACS,d and Jürgen Frevert PhDe

aDepartment of Cosmetic Science, University of Hamburg, Hamburg, Germany bDepartment of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand cClinica de Dermatologia, Hospital do Servidor Municipal de São Paulo, São Paulo, Brazil dOtolaryngology and Head and Neck Surgery, University of California, San Francisco, CA eFormerly of Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany

search support from Merz Pharmaceuticals, and is a speaker for Allergan, Merz Pharmaceuticals, andTheraskin. C. Maas is an investigator for Merz Pharmaceuticals GmbH and Allergan, and has acted an advisor to Merz. J. Frevert is a former employee of, and current consultant for, Merz Pharmaceuticals GmbH.

ACKNOWLEDGMENTS

This review was supported by Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany. Medical writing support, under the direction of the authors, was provided for early drafts by Claire Cairney PhD of CMC CONNECT, a division of Complete Medical Communications Ltd, Glasgow, UK, funded by Merz Pharmaceuticals GmbH, in accordance with Good Publication Practice (GPP3) guidelines.

REFERENCES

  1. Allergan Inc. Highlights of prescribing information - Botox®. 2017. Avail- able from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/ 103000s5302lbl.pdf. Accessed 2 October 2018.
  2. Frevert J. Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D. 2015;15(1):1-9.
  3. American Society for Dermatologic Surgery. Survey on dermatologic proce- dures. 2017. Available from: https://www.asds.net/portals/0/PDF/procedure- survey-results-presentation-2017.pdf. Accessed 20 September 2018.
  4. American Society of Plastic Surgeons. Plastic Surgery Statistics Report. 2017. Available from: https://www.plasticsurgery.org/documents/News/Sta- tistics/2017/plastic-surgery-statistics-full-report-2017.pdf. Accessed 2 Octo- ber 2018.
  5. Fagien S, Carruthers JD. A comprehensive review of patient-reported satis- faction with botulinum toxin type a for aesthetic procedures. Plast Reconstr Surg. 2008;122(6):1915-1925.
  6. Ipsen Biopharm Ltd. Highlights of prescribing information - Dysport®. 2017. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/ label/2017/125274s109lbl.pdf. Accessed 2 October 2018.
  7. Galderma (U.K.) Ltd. Azzalure® Summary of Product Characteristics. 2018. Available from: https://www.medicines.org.uk/emc/product/6584/smpc. Ac- cessed 2 October 2018.
  8. Ipsen Biopharm Ltd. Dysport® 500 U Summary of Product Characteristics. 2017. Available from: https://www.medicines.org.uk/emc/medicine/32114. Accessed 2 October 2018.
  9. Merz Pharma UK Ltd. XEOMIN® (50/100/200) Summary of Product Char- acteristics. 2017. Available from: http://www.medicines.org.uk/emc/medi- cine/24582. Accessed 2 October 2018.
  10. Merz Pharmaceuticals LLC. Highlights of prescribing information – Xeo- min®. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_ docs/label/2018/125360s073lbl.pdf. Accessed 2 October 2018.
  11. Merz Pharma UK Ltd. Bocouture® Summary of Product Characteristics. 2018. Available from: https://www.medicines.org.uk/EMC/medicine/23251/ SPC/Bocouture/. Accessed 2 October 2018.
  12. Allergan Ltd. Botox® 100 U Summary of Product Characteristics. 2017. Avail- able from: http://www.medicines.org.uk/EMC/medicine/112/SPC/. Accessed 2 October 2018.
  13. Allergan Ltd. Vistabel® Summary of Product Characteristics. 2018. Available from: https://www.medicines.org.uk/emc/product/187/smpc. Accessed 2 October 2018.
  14. Frevert J, Ahn KY, Park MY, Sunga O. Comparison of botulinum neurotoxin type A formulations in Asia. Clin Cosmet Investig Dermatol. 2018;11:327-331.
  15. Evolus Inc. Nuceiva product monograph. 2018. Available from: https://pdf. hres.ca/dpd_pm/00046932.PDF. Accessed 11 October 2018.
  16. Inoue K, Fujinaga Y, Watanabe T, et al. Molecular composition of Clostridium botulinum type A progenitor toxins. Infect Immun. 1996;64(5):1589-1594.
  17. Eisele KH, Fink K, Vey M, Taylor HV. Studies on the dissociation of botulinum neurotoxin type A complexes. Toxicon. 2011;57(4):555-565.
  18. Frevert J. Xeomin: an innovative new botulinum toxin type A. Eur J Neurol. 2009;16 (Suppl. 2):11-13.
  19. Wanitphakdeedecha R, Ungaksornpairote C, Kaewkes A, Sathaworawong A, Vanadurongwan B, Lektrakul N. A pilot study comparing the efficacy of two formulations of botulinum toxin type A for muscular calves contouring. J Cosmet Dermatol. 2018:[Epub ahead of print].
  20. Zhang L, Lin WJ, Li S, Aoki KR. Complete DNA sequences of the botulinum neurotoxin complex of Clostridium botulinum type A-Hall (Allergan) strain. Gene. 2003;315:21-32.
  21. Glogau RG, Waugh JM. Preclinical transcutaneous flux experiments using a macromolecule transport system (MTS) peptide for delivery of botulinum toxin type A. Poster presented at the 66th Annual Meeting of the American Academy of Dermatology; February 1–5, 2008; San Antonio, TX. Revance Therapeutics, Inc. 2008. Available from: http://www.revance.com/pdfs/Pre- clinical-transcutaneous-flux-experiment-type-a.pdf. Accessed 12 September 2018.
  22. Gu S, Rumpel S, Zhou J, et al. Botulinum neurotoxin is shielded by NTNHA in an interlocked complex. Science. 2012;335(6071):977-981.
  23. Fujinaga Y, Matsumura T, Jin Y, Takegahara Y, Sugawara Y. A novel function of botulinum toxin-associated proteins: HA proteins disrupt intestinal epithelial barrier to increase toxin absorption. Toxicon. 2009;54(5):583-586.
  24. Matsumura T, Sugawara Y, Yutani M, et al. Botulinum toxin A complex ex- ploits intestinal M cells to enter the host and exert neurotoxicity. Nat Com- mun. 2015;6:6255.
  25. Ghosal KJ, Patel K, Singh BR, Hale ML. Role of critical elements in botulinum neurotoxin complex in toxin routing across intestinal and bronchial barriers. PLoS One. 2018;13(7):e0199524.
  26. Cheng LW, Onisko B, Johnson EA, et al. Effects of purification on the bio- availability of botulinum neurotoxin type A. Toxicology. 2008;249(2-3):123- 129.
  27. Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010;4:325-332.
  28. Grein S, Mander GJ, Fink K. Stability of botulinum neurotoxin type A, devoid of complexing proteins. Botulinum J. 2011;2(1):49-57.
  29. Soares DJ, Dejoseph LM, Zuliani GF, Liebertz DJ, Patel VS. Impact of postreconstitution room temperature storage on the efficacy of incobotu- linumtoxinA treatment of dynamic lateral canthus lines. Dermatol Surg. 2015;41(6):712-717.
  30. Joshi SG, Elias M, Singh A, et al. Modulation of botulinum toxin-induced changes in neuromuscular function with antibodies directed against recom- binant polypeptides or fragments. Neuroscience. 2011;179:208-222.
  31. Dressler D, Wohlfahrt K, Meyer-Rogge E, Wiest L, Bigalke H. Antibody-in- duced failure of botulinum toxin a therapy in cosmetic indications. Dermatol Surg. 2010;36 (Suppl. 4):2182-2187.
  32. Torres S, Hamilton M, Sanches E, Starovatova P, Gubanova E, Reshetnikova T. Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medi- cine: five case reports. Clin Cosmet Investig Dermatol. 2014;7:11-17.
  33. Lee J-C, Yokota K, Arimitsu H, et al. Production of anti-neurotoxin antibody is enhanced by two subcomponents, HA1 and HA3b, of Clostridium botulinum type B 16S toxin-haemagglutinin. Microbiology. 2005;151(Pt 11):3739-3747.
  34. Go?schel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H. Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies – therapeutic conse- quences. Exp Neurol. 1997;147(1):96-102.
  35. Kukreja R, Chang T-W, Cai S, et al. Immunological characterization of the subunits of type A botulinum neurotoxin and different components of its associated proteins. Toxicon. 2009;53(6):616-624.
  36. Wang L, Sun Y, Yang W, Lindo P, Singh BR. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon. 2014;82:52-60.
  37. Stengel G, Bee EK. Antibody-induced secondary treatment failure in a pa- tient treated with botulinum toxin type A for glabellar frown lines. Clin Interv Aging. 2011;6:281-284.
  38. Blu?mel J, Frevert J, Schwaier A. Comparative antigenicity of three prepara- tions of botulinum neurotoxin type A in the rabbit. Neurotox Res. 2006;9:238.
  39. Kazerooni R. Decrease in therapeutic effect among botulinum neurotoxin type A agents: analysis of the FDA adverse event reporting system data- base. Paper presented at: TOXINS 2019. Basic science and clinical aspects of botulinum and other neurotoxins; 16-19 January 2019.
  40. Frevert J, Groenewald C. Presence of clostridial DNA in botulinum toxin products. Toxicon. 2015;93 (Suppl.):S28.
  41. Frevert J. Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/ Azzalure®, and Xeomin®/Bocouture®. Drugs R D. 2010;10(2):67-73.
  42. Goodnough MC, Johnson EA. Stabilization of botulinum toxin type A during lyophilization. Appl Environ Microbiol. 1992;58(10):3426-3428.
  43. Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology. 1995;45(9):1743-1746.
  44. Jost WH, Benecke R, Hauschke D, et al. Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders. Drug Des Devel Ther. 2015;9:1913-1926.
  45. Kerscher M, Yutskovskaya Y, Flynn TC. IncobotulinumtoxinA in esthetics. J Drugs Dermatol. 2013;12(6):e111-120.
  46. Kerscher M, Rzany B, Prager W, Turnbull C, Trevidic P, Inglefield C. Efficacy and Safety of IncobotulinumtoxinA in the Treatment of Upper Facial Lines: Results From a Randomized, Double-Blind, Placebo-Controlled, Phase III Study. Dermatol Surg. 2015;41(10):1149-1157.
  47. Streker M, Luebberding S, Krueger N, Harrington L, Kerscher M. Patient- reported outcomes after incobotulinumtoxinA treatment for upper facial wrinkles. Dermatol Surg. 2015;41 (Suppl. 1):S29-38.
  48. Kane MA, Gold MH, Coleman WP, 3rd, et al. A randomized, double-blind trial to investigate the equivalence of incobotulinumtoxina and onabotulinumtoxi- nA for Glabellar Frown Lines. Dermatol Surg. 2015;41(11):1310-1319.
  49. Prager W, Wissmuller E, Kollhorst B, Williams S, Zschocke I. Comparison of two botulinum toxin type A preparations for treating crow's feet: a split- face, double-blind, proof-of-concept study. Dermatol Surg. 2010;36 (Suppl. 4):2155-2160.
  50. Coleman WP, III, Sattler G, Weissenberger P, Hast MA, Hanschmann A. Safety of incobotulinumtoxinA in the treatment of facial lines: Results from a pooled analysis of randomized, prospective, controlled clinical studies. Der- matol Surg. 2017;43:S293-S303.
  51. Evidente VGH, Fernandez HH, LeDoux MS, et al. A randomized, double-blind study of repeated incobotulinumtoxinA (Xeomin®) in cervical dystonia. J Neural Transm. 2013;120(12):1699-1707.
  52. Wissel J, Bensmail D, Ferreira JJ, et al. Safety and efficacy of incobotulinum- toxinA doses up to 800 U in limb spasticity: The TOWER study. Neurology. 2017;88(14):1321-1328.
  53. Kanovsky? P, Slawek J, Denes Z, et al. Efficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complex- ing proteins; NT 201) in post-stroke upper limb spasticity. J Rehabil Med. 2011;43(6):486-492.
  54. Kanovsky? P, Slawek J, Denes Z, et al. Efficacy and safety of botulinum neu- rotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol. 2009;32(5):259-265.
  55. Truong DD, Gollomp SM, Jankovic J, et al. Sustained efficacy and safety of repeated incobotulinumtoxinA (Xeomin®) injections in blepharospasm. J Neural Transm (Vienna). 2013;120(9):1345-1353.
  56. Dressler D, Adib SF, Bigalke H. IncobotulinumtoxinA (Xeomin) can produce antibody-induced therapy failure in a patient pretreated with abobotulinum- toxinA (Dysport). J Neural Transm. 2014;121(7):769-771.
  57. Dressler D, Pan L, Adib Saberi F. Antibody-induced failure of botulinum toxin therapy: re-start with low-antigenicity drugs offers a new treatment opportu- nity. J Neural Transm (Vienna). 2018;125(10):1481-1486.
  58. Hefter H, Hartmann C, Kahlen U, Moll M, Bigalke H. Prospective analysis of neutralising antibody titres in secondary non-responders under continu- ous treatment with a botulinumtoxin type A preparation free of complexing proteins-a single cohort 4-year follow-up study. BMJ Open. 2012;2(4).
  59. Carruthers J, Solish N, Humphrey S, et al. Injectable daxibotulinumtoxina for the treatment of glabellar lines: a phase 2, randomized, dose-ranging, double-blind, multicenter comparison with onabotulinumtoxina and placebo. Dermatol Surg. 2017;43(11):1321-1331.
  60. Jankovic J, Truong D, Patel AT, et al. Injectable daxibotulinumtoxinA in cervi- cal dystonia: a phase 2 dose-escalation multicenter study. Mov Disord Clin Pract. 2018;5(3):273-282.
  61. Allergan announces results of higher dose Botox® cosmetic (onabotulinum- toxinA) for the treatment of moderate to severe glabellar lines. PRNews- wire, 14 September 2018. Available from: https://www.prnewswire.com/ news-releases/allergan-announces-results-of-higher-dose-botox-cosmetic- onabotulinumtoxina-for-the-treatment-of-moderate-to-severe-glabellar- lines-300713102.html.
  62. Maas C. Safety and efficacy of escalating doses of incobotulinumtoxinA for extended treatment of glabellar frown lines: a randomized, double-blind study. J Am Acad Dermatol. 2018;79(3):AB250.
  63. Thistle F. Greenhouse gas emissions and botulinum neurotoxin packaging. Hospital Pharmacy Europe. 2012; 64:27-30.

AUTHOR CORRESPONDENCE

Ju?rgen Frevert PhD Juergen.Frevert@merz.de