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Botulinum Toxin Products Overview
A. Carruthers, MD, FRCPC1; J. Carruthers, MD, FRCS(C), FRC(Ophth)2
In 1982, one of us (JC) first brought the concept and the application of botulinum toxin (BTX) for clinical use in ophthalmology to Health Canada. This submission was approved and experimental use for misaligned eyes began in 1983. The subsequent use for benign essential blepharospasm led to its cosmetic use, which we developed in 1987. Following 25 years of therapeutic applications and over 20 years of cosmetic experience with this neurotoxin in Canada, its uses and development of new products continue to expand.1
BTX Products Under Development in North AmericaIn addition to the original product, several BTX injectables are in clinical development in North America (Table 1).
BOTOX® Cosmetic/Vistabel®/Vistabex® (Allergan Inc.)
This is the original botulinum toxin type A (BTX-A) product, which was initially purified in crystalline from by Shantz and adapted for clinical use by Scott in San Francisco.1 There was a formulation change in 1997 in order to reduce the amount of immunogenic protein in the material, but there have been no modifications since. In order to gain European regulatory approval, production of a vial containing 50 units was required; it was previously only available as a 100 unit vial. BTX has a broad range of approvals for both therapeutic and cosmetic indications. This neurotoxin currently captures 85% of the worldwide BTX market and the majority of scientific peer reviewed articles on BTXs are about BOTOX®.1
Dysport®/Reloxin® (Ipsen Inc./ marketed for cosmetic indications in North America by Medicis Inc.)
This formulation of type A neurotoxin is approved in over 65 countries, although, at the time of writing, it has not been approved for cosmetic use in North America or Europe. The difference between Dysport®/Reloxin® and its original counterpart is that BOTOX® is purified by repeated precipitation and redissolution, whereas Dysport®/Reloxin® is produced by purification using a column separation method.
PurTox® (Mentor Corporation)
Complexing proteins are therapeutically superfluous and present a high foreign protein load, which may in turn increase the potential for eliciting an immune response. PurTox® is an uncomplexed type A neurotoxin (i.e., the neurotoxin molecule is stripped of its complexing proteins) that is licensed to Mentor Corporation. It is currently in Phase 3 testing for glabellar frown lines, as well as in various stages of development for therapeutic indications. The neurotoxin units of PurTox® appear to be slightly less effective than that of BOTOX®, and they are subjected to different purification processes.
NT-201/ Xeomin® (Merz Pharmaceuticals)
This uncomplexed BTX-A is produced by Merz Pharmaceuticals and has received approval for the treatment of blepharospasm and cervical dystonia in some European countries, as well as in Mexico and Argentina. Currently, regulatory approval for the esthetic indication of treating glabellar frown lines has been obtained in Argentina only. In terms of potency, NT-201 appears to exhibit a 1:1 dose ratio when compared with BOTOX®, and it has a smaller molecule relative to the other BTX products discussed. In studies that compared NT-201/Xeomin® with BOTOX® for therapeutic indications, no significant differences were detected in both safety and efficacy.4,5 Jost, et al. proposed that the absence of complexing proteins in NT-201 does not hinder its performance.4 Instead, uncomplexed forms of BTX-A may result in purer formulations that can potentially reduce sensitization and antibody formation, as well as improve clinical efficacy; this has been a concern with past formulations containing complexing proteins.
Myobloc®/NeuroBloc® (Solstice Neurosciences Inc./Eisai Co., Ltd.)
Myobloc®/NeuroBloc® is the only available botulinum toxin type B (BTX-B) product, and cervical dystonia is currently its sole approved indication. This BTX-B neurotoxin was originally developed by Elan Pharmaceuticals, but it is now produced by Solstice Neurosciences Inc.; Eisai Co., Ltd. holds the commercial rights to the product in Japan, Russia, European Union nations, as well as other countries. Myobloc®/NeuroBloc® is approved in Canada, US and Europe for cervical dystonia, and is available as a liquid with an acidic pH level of 5.5 to 5.6. Due to the elevated acidity, patients may find injections to be very painful. In addition, the units are substantially less effective when compared with BTX-A units. For example, in cervical dystonia, the ratio is estimated to be approximately 50:1, whereas for glabellar frown lines, the ratio is 100:1. When used for the temporary correction of glabellar frown lines, the clinical duration did not appear to be as long-lasting as BOTOX®.6,7 However, Myobloc® does appear to exhibit a more rapid onset of action and a greater area of diffusion.8 Associated adverse effects, such as dry mouth and dysphagia, are generally mild-to-moderate, transient, and more common at higher doses.
Other BTX Products Under Global Development
CBTX-A (Lanzhou Institute of Biological Products)
This is the only BTX-A product that is approved in the People’s Republic of China; as well, it is marketed in Brazil as Prosigne®. The major difference between this preparation and the other BTX-A products is that a bovine gelatin protein is added to the vial in order to prevent the BTX from sticking to the wall of the vial, syringe, etc. Human serum albumin is almost always used, but in the case of CBTX-A, the gelatin utilized is of bovine derivation, which has the potential to induce allergic reactions, or possibly bovine spongiform encephalopathy, a neurological disease commonly known as “mad cow disease”.
CNBTX-A (Nanfeng Medical Science and Technology Development Co., Ltd.)
Although product orders may be placed via the internet, CNBTX-A is neither licensed nor approved in any country. The potency of CNBTX-A was recently investigated and found to contain significantly higher levels of botulinum neurotoxin than listed on the product’s label, which could constitute a severe health risk for patients.9 We are not aware of any additional details about this preparation.
Neuronox® (Medy-Tox Inc.)
This BTX-A preparation is produced by Medy-Tox in South Korea. It is widely used in Korea and South East Asia, and it appears to be effective. We are not aware of any additional details except that the worldwide licensing of its cosmetic use has been acquired by Q-Med Inc. (Sweden).
The use of botulinum toxin is continuing to increase rapidly, with a worldwide growth in sales that is forecasted to be in excess of 20% annually for the near future. A milestone was reached in 2006 when BOTOX® became a billion dollar drug for Allergan Inc.; the company continues to retain 85% of the worldwide neurotoxin market. However, competing products will receive regulatory approval for esthetic indications in the near future. Reloxin® will likely be approved in the US towards the end of 2008 or early 2009, and NT-201 and PurTox® are expected to follow suit in a couple of years. Other neurotoxins not discussed in this overview will undoubtedly appear, especially as the applications of BTX continue to expand.
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Last modified: Wednesday, 06-Aug-2014 12:23:13 MDT