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

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

Abstract

Aesthetic dermatologic applications of botulinum neurotoxin (BoNT), including treatment of glabellar lines, horizontal forehead lines, and crow’s feet, were the most common non-surgical cosmetic procedures in the US in 2017, with high levels of subject satisfaction. Since the first BoNT type A (BoNT-A) formulation was approved in 1989, the number of formulations available on the world’s commercial markets has increased and new approvals are expected. BoNT is produced by Clostridium botulinum in nature as part of a large protein complex. However, the unnecessary clostridial proteins, which dissociate from BoNT under physiological conditions with a half-life of less than 1 minute, have no role in clinical applications. Data demonstrate that BoNT administration can elicit an immunological response, leading to production of neutralizing antibodies that can be associated with reduced efficacy or treatment non-response. As repeat treatments are required to maintain efficacy, clinicians should be aware of the possibility of antibody development and choose a BoNT with the lowest risk of immunogenicity. IncobotulinumtoxinA is manufactured using advanced technology to precisely isolate the pure BoNT without unnecessary clostridial proteins, and with low immunogenicity and high specific activity. In incobotulinumtoxinA clinical studies, no previously BoNT-naïve subjects developed neutralizing antibodies, and there was no secondary non-response to incobotulinumtoxinA treatment. Here we review the role of unnecessary clostridial proteins in BoNT-A and discuss the unique incobotulinumtoxinA manufacturing and purification process with a focus on the implications for use in aesthetic medicine. J Drugs Dermatol. 2019;18(1):52-57.

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INTRODUCTION

Since the first botulinum neurotoxin (BoNT) formulation was approved by the US Food and Drug Administration (FDA) in 1989 1,2, the number of approved indications, and BoNT products commercially available worldwide, has in- creased. Aesthetic dermatologic applications of BoNT were the most common non-surgical cosmetic procedures in the US in 2017,3,4 and have high levels of patient satisfaction.5 The three most widely used and commercially available BoNT typeA (BoNT-A) formulations are: abobotulinumtoxinA (Dysport®/ Azzalure®, Ipsen Biopharm),6-8 incobotulinumtoxinA (Xeomin®/ Bocouture®, Merz Pharmaceuticals GmbH),9-11 and onabotu- linumtoxinA (Botox®/Vistabel®, Allergan Inc.)1,12,13 (approved indications differ by product and country, see individual product listings).2 Several new BoNT-A formulations have recently been introduced in different countries,14,15 however, incobotulinum- toxinA currently remains the only BoNT formulation approved in commercial markets worldwide that was intentionally designed to contain only the required therapeutic component, the pure BoNT, free from unnecessary clostridial proteins.14 Here we discuss the role of these unnecessary proteins in BoNT-A, and the unique manufacturing and purification process for incobotulinumtoxinA, with a focus on the implications for use in aesthetic medicine.

Role of Unnecessary Clostridial Proteins

All BoNT-A products discussed here contain BoNT-A from a C. botulinum Hall strain,2 which is produced in nature (its native form) as part of a larger multimeric complex with accessory proteins.16,17 Three BoNT-A complexes are formed, comprised of BoNT-A and a non-toxic non-hemagglutinin (NTNHA) protein in the smaller 300 kDa M complex, with the addition of several hemagglutinin (HA) proteins in the larger 500 kDa L and 900 kDa LL complexes.16,17 IncobotulinumtoxinA contains only the 150 kDa BoNT-A active therapeutic component purified from the therapeutically unnecessary clostridial proteins.18 In contrast, abobotulinumtoxinA, onabotulinumtoxinA, and, the newer addition, prabotulinumtoxinA (Nabota®, Daewong Ther- apeutics, Korea/Evolus®, Evolus Inc., Europe, USA/Nuceiva®, Evolus Inc., Canada) all contain the HA and NTNHA proteins complexed with the 150 kDa BoNT.2,14,19,20 Investigational drug candidate daxibotulinumtoxinA (RT002, Revance Therapeutics 

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