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The future of neuromodulators in aesthetic medicine


Summary and key features

  • Aesthetic use of botulinum toxin type A (BoNT-A) started in the glabella and upper face but has now expanded into the mid and lower face, including masseters and neck.

  • Aesthetic facial shaping of the upper and lower face is possible and popular with the combined use of BoNT-A and three-dimensional fillers, as well as laser and energy-based devices.

  • New developments in the formulation of the BoNT-A molecule have produced several novel candidate molecules, which have shown increased and decreased longevity of response, as well as improved ease of use.

  • Increased understanding of the central effects and mechanisms of BoNT-A action is leading to a remarkable new appreciation for self-esteem, depression, and pain applications, as well as for the treatment of dystonias and the many cosmetic uses.

Introduction

Botulinum toxin type A (BoNT-A) has been utilized for various clinical purposes since the 1960s and the safety data associated with its use has been well established. The brand name Botox was first approved by the United States Food and Drug Administration (US FDA) in 1989 for strabismus, blepharospasm, and cervical dystonia, and since then the market and technology have continued to grow. The use of BoNT-A for cosmetic purposes was introduced in 1991 to improve facial rhytids and continues to be the most common nonsurgical cosmetic procedure performed in the United States and the world as a whole. Remarkably this use has continued to expand despite economic recessions and other global adverse events. Clinical studies began by treating only glabellar frown lines, but work on other sites, such as crow’s feet and forehead lines, swiftly followed. Over time, the percentage of millennial patients, as well as male patients using neuromodulators has also continued to expand. The regulatory oversight of the use of BoNT-A has gradually caught up with physicians’ advances and now there are multiple cosmetic indications approved in most parts of the world. It can be anticipated that with evolving techniques, broadened clinical indications, and the creation of new and improved products, the popularity of neuromodulators will continue to generate attention from patients and physicians alike.

Since the origin of the concept of neuromodulators for clinical use, a paradigm shift has been initiated in cosmetic medicine. Facial rejuvenation has now become minimally invasive, safer, affordable, and more effective with the emergence of new technology. Despite the old adage, “It is difficult to make predictions, especially about the future!” This chapter will address the evolving future of BoNT-A in the following areas: expansion of current uses, changes to the molecule and formulation, and new techniques and indications.

Expansion of current uses

There are 4 FDA-approved BoNT-A products commercially available in the United States for cosmetic use, the newest addition being (prabotulinumtoxinA-xvfs/Jeuveau) ( Table 28.1 ). Even though FDA approval is limited for the most part to glabellar rhytid use, many of the physicians who were involved in the early cosmetic application of BoNT-A experimented with its use in different areas. As a result, many cosmetic physicians are comfortable using these products for several “off-label” indications including forehead lines, lateral canthal lines, bunny lines, mental dimpling, down-turned angle of the mouth, masseter hypertrophy, and platysmal bands. It was also learned that the facial muscles need to be treated with respect and therefore low doses should be used at least initially and particularly in the lower face. This expansion of the use of BoNT-A depends on the effect of reducing the contractility and resting tone in treated muscles; other actions include reducing glandular secretions and possibly neocollagenesis, though this needs further study.

TABLE 28.1
Currently FDA Approved Neurotoxins Available in the United States
This table has been adapted and revised from the following original publication: Labadie, J. G., Dover, J., & Alam, M. (2020). New toxins and fillers on the horizon: implications for both patients and practices. Advances in Cosmetic Surgery, 3 (1), 123–134.
CURRENTLY FDA APPROVED NEUROTOXINS AVAILABLE IN THE UNITED STATES
Commercial Name Botox/Botox Cosmetic/Vistabel/Vistabex (Allergan, Inc., Irvine, California, USA) Dysport/Reloxin/Azzalure (Galderma Laboratories, Switzerland) Xeomin/Bocoture (Merz Pharmaceuticals, Germany) Jeuveau/Nabota (Evolus, Newport Beach, California, USA) MyoBloc/NeuroBloc (Solstice Neurosciences, Inc., Louisville, Kentucky, USA)
Background Botox is the trade name for onabotulinumtoxinA and was first FDA approved in 1989 for the treatment of cervical dystonia, severe primary axillary hyperhidrosis, blepharospasm, neurogenic detrusor overactivity (urinary incontinence), chronic migraine, upper limb spasticity, and moderate-to-severe glabellar lines. Of note, there is anticipation of Botox prefilled syringes coming to the market in the next several years, in order to improve efficiency and reduce contamination risk. Dysport is the trade name for abobotulinumtoxinA. It was approved by the FDA in 2009 for the treatment of cervical dystonia and moderate-to-severe glabellar lines. In contrast to Botox which is purified by repeated precipitation and re-dissolution, Dysport is purified by a column separation method, which may account for increased toxin spread. In addition, the Dysport dose ratio is slightly higher than that of Botox at a ratio of approximately 3:1. Xeomin is the trade name for incobotulinumtoxinA, which became FDA approved in 2011 for moderate-to-severe glabellar lines in adults. Xeomin has a similar dose ratio to that of Botox, however it does not contain complexing proteins. It is marketed as a potentially purer formulation, which could reduce the theoretical risk of antibody formation and ultimately resistance, however additional studies are needed to verify this hypothesis. Jeuveau is the trade name for prabotulinumtoxinA-xvfs. This product is new to the US scene, as it was approved in April of 2019 for the treatment of moderate-to-severe glabellar lines. However, prabotulinumtoxinA has been part of the global market since 2014 under the tradename Nabota by Daewoong Pharmaceuticals (Seoul, South Korea). Jeuveau was originally marketed as the “newtox,” the newest toxin in the US, but the FDA recently requested that the company no longer use this term. There have been claims of faster onset of action, however further investigation is needed to determine if there are true differences between available brands. MyoBloc is the trade name for rimabotulinumtoxinB. It is the only botulinum toxin type B commercially available in the United States. However, it is not approved for cosmetic use, only cervical dystonia. The data for MyoBloc in the correction of glabellar lines was not promising for cosmetic use, as it demonstrated more painful injections with shorter duration of effects.
Strain onabotulinumtoxinA abobotulinumtoxinA incobotulinumtoxinA prabotulinumtoxinA-xvfs rimabotulinumtoxinB
Company Allergan Galderma Laboratories Merz Pharmaceuticals Evolus Solstice Neurosciences
Approval (Year) FDA (1989) FDA (2009) FDA (2010) FDA (2019) FDA (2009)
Contraindications

  • Neuromuscular disorders that exacerbated clinical effects of treatment

  • Hypersensitivity to any BoNT-A product or excipient

  • Infection at site of injection

  • Neuromuscular disorders that exacerbated clinical effects of treatment

  • Hypersensitivity to any BoNT-A product or excipient

  • Infection at site of injection

  • Allergy to cow’s milk

  • Neuromuscular disorders that exacerbated clinical effects of treatment

  • Hypersensitivity to any BoNT-A product or excipient

  • Infection at site of injection

  • Neuromuscular disorders that exacerbated clinical effects of treatment

  • Hypersensitivity to any BoNT-A product or excipient

  • Infection at site of injection

  • Neuromuscular disorders that exacerbated clinical effects of treatment

  • Hypersensitivity to any BoNT-A product or excipient

  • Infection at site of injection

Molecular Weight 900 kD 500–900 kD 150 kD 900 kD 700 kD
Strength 1:1 3:1 1:1 1:1 50:1
Formulation Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Liquid
Mode of Action SNAP-25 SNAP-25 SNAP-25 SNAP-25 VAMP
Units per Vial 50, 100, 200 300, 500 50, 100 100 2500; 5000; 10,000
Excipients Human serum albumin, NaCl Human serum albumin, lactose Human serum albumin, sucrose Human serum albumin, NaCl Human serum albumin, NaCl, disodium succinate, water
Storage

  • Before dilution: 2°C–8°C or <5°C

  • After dilution: 2°C–8°C

2°C–8°C <25°C 2°C–8°C 2°C–8°C

Changes to the molecule and formulation

New products on the horizon

As with any successful drug, such as BoNT-A, there is a strong temptation to try to “improve” it. The result of all the research, from Dr. Alan Scott’s original studies on animals in the 1970s up to the present time, has demonstrated that Dr. Schantz’s original formulation, used by Scott, was in many respects optimal. It became even more so when Allergan removed much of the associated protein in 1997. BoNT-A has a favorable duration in comparison with the other serotypes and seems to be durable and not as fragile, as initially thought. On a global scale, several non-US FDA products are gaining worldwide attention, and it is plausible that many of these products will break into the US landscape soon. Each of these products are further explained in Table 28.2 .

TABLE 28.2
Neurotoxin Products on the Horizon for the US Market
This table has been adapted and revised from the following original publication: Labadie, J. G., Dover, J., Alam, M. (2020). New toxins and fillers on the horizon: implications for both patients and practices. Advances in Cosmetic Surgery, 3 (1), 123–134.
NEUROTOXINS ON THE HORIZON FOR THE US MARKET
Commercial Name DaxibotulinumtoxinA/RT002 (Revance Therapeutics Inc., Newark, California, USA) Botulax /BoNT/A-DP (Croma-Pharma, Austria) Innotox/NivobotulinumtoxinA/MT10109L (Medy-Tox Inc., South Korea) Nabota Relatox Coretox Lantox/Prosigne/Redux/ChinaTox Meditoxin/Neuronox
Background DaxibotulinumtoxinA or RT002 is currently undergoing clinical trials in the US. It is unique in that it uses a positively charged peptide to bind with the negatively charged portion of its toxin molecule, potentially allowing for longer-lasting results. As such, it will likely be marketed by Revance as a “long-acting neuromodulator.” Recently published data demonstrated that 30.8% of patients given a 40-unit dose maintained improvement in investigator and patient-assessed glabellar line severity scores 6 months post-treatment. Future studies are required to determine the true efficacy and longevity of treatment (Carruthers 2017, Jankovic 2018, Benedetto 2019, Bertucci 2020). Botulax, a BoNT-A is currently available for use in non-US markets for the treatment of glabellar lines, blepharospasm, limb spasticity and spastic foot deformity (Benedetto 2019). However, it is projected to reach the US market soon, as Croma-Pharma, has acquired the North American rights to Botulax and US clinical trials are currently under way. Innotox is the trade name for NivobotulinumtoxinA and is the first neurotoxin that comes in an already diluted liquid formulation (0.4 mL = 1 unit). The molecular weight and diffusion capacity of Innotox have been reported as similar to that of Botox. This liquid formulation is marketed as a way to increase efficiency, as well as reduce dilution and contamination. Allergan and Medy-Tox are currently in collaboration and hope to bring this product to the US market by 2022. Recruitment for US clinical trials is currently underway. TBD TBD TBD TBD TBD
Strain DaxibotulinumtoxinA CBFC26 Clostridium botulinum type A (Hall group AT3502) prabotulinumtoxinA Botulinum toxin type A + hemagglutinin Clostridium botulinum type A (Hall group AT3502) CBTX-A Clostridium botulinum type A (Hall group AT3502)
Company Revance Therapeutics Hugel Inc/Croma Medytox Inc. Daewoong Pharmacy NGO Microgen Medytox Inc. Lanzhou Institute of Biological Products Medytox Inc.
Molecular Weight 150 kD 900 kD 900 kD 900 kD 900 kD 150 kD 900 kD 900 kD
Formulation Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Liquid formulation Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline Powder to be reconstituted in normal saline
Mode of Action SNAP-25 SNAP-25 SNAP-25 SNAP-25 SNAP-25 SNAP-25 SNAP-25 SNAP-25
Units per Vial TBD 100, 150, 200 0.1 mL = 4U 50, 100, 200 50, 100 50, 100, 200 100 50, 100, 150, 200
Excipients Proprietary peptide Human serum albumin, NaCl Human serum albumin, NaCl Human serum albumin, NaCl Hemagglutinin, gelatin, maltose Human serum albumin, NaCl Gelatin, dextran, sucrose Human serum albumin, NaCl
Storage TBD (may not require refrigeration during storage or shipping) 2°C –8°C 2°C–8°C 2°C–8°C 2°C–8°C 2°C–8°C 2°C–8°C -15 or at 2°C–8°C

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