Introduction

Neuronox^® (Medytox Inc., Ochang, South Korea) is a botulinum toxin type A (BoNT-A) product first approved in 2006 by the Korean Food and Drug Administration. Since then, it has been approved under different brand names as Botulift^®, Siax^®, Cunox^®, and Meditoxin^® in 23 countries world wide (Fig. 8.1). Among currently available BoNT-A products, Neuronox^® seems to be one of the viable alternatives to Botox^® in terms of microbiological, physicochemical, and biochemical features, and clinical interchangeability in 1 : 1 dose ratio.

Figure 8.1 Neuronox^® is marketed under different brand names such as Botulift^®, Siax^®, Cunox^®, and Meditoxin^®.

Microbiological, physicochemical, and biochemical profiles

Considering that botulinum toxin is a biological agent produced in living cells, one ought to first analyze the bacterial strain that produced the toxin itself. In the late 1970s, Dr Kyu-Hwan Yang, a microbiologist brought Clostridium botulinum to the Korean Advanced Institute of Science and Technology (KAIST) with him after several years of research at the University of Wisconsin. While the C. botulinum produced at the University of Wisconsin became the source of Oculinum^® – the first licensed botulinum toxin product, later renamed Botox^®, the exact same strain at KAIST became the foundation of botulinum toxin research in Korea as well as the source of Neuronox^®, which was formulated by a group of scientists from KAIST, who later founded Medytox Inc. As a result the C. botulinum type A Hall strain used by Medytox Inc. (GenBank accession number DQ409059) is exactly the same bacterial strain as that used by Allergan (AF488749, 488748, 488747, AF488746, AF488745), and there is no difference between the two deduced amino acid sequences derived from the DNA sequence of the type A toxin complex.

However, differences in manufacturing processes, such as purification and filtration, can result in differences in the bulk toxin even amongst those from the same culture solution. One important physicochemical feature potentially affected by such processes would be the molecular weight. The size exclusion high-performance liquid chromatography (SE-HPLC) analysis of Neuronox^® yields a single peak in the chromatogram with an average molecular weight of 904 ± 7 kDa. This is highly comparable with that of Allergan: 880kDa by SE-HPLC analysis and 925 ± 45 kDa by light-scattering analysis.

In addition, the botulinum toxin is formulated in different ways in the final stages. Neuronox^® is formulated using a freeze-drying method, whereas Botox^® is formulated as vacuum-dried powder. Nevertheless, Neuronox^® ultimately has a similar formulation to Botox^®, with one vial containing 100 mouse units of the purified toxin complex, 0.9 mg of sodium chloride, and 0.5 mg of human serum albumin.

It is still unclear whether the origin of the bacterial strain, molecular weight, or product formulation is truly clinically significant. But such specifications supported by clinical data could provide outline guidelines to practicing physicians.

Clinical studies for Neuronox^®

The safety and efficacy of Neuronox^® were compared with Botox^® in two randomized, double-blind studies, at a 1 : 1 dose ratio, for the treatment of essential blepharospasm and spasticity in children with cerebral palsy (Kim et al and Yoon et al). Neuronox^® was proven to be non-inferior to Botox^® in both studies, and there was no significant difference in the safety profiles. Although published studies on Neuronox^® are limited to the therapeutic area owing to its recent introduction to the market, several clinical studies using Neuronox^® in aesthetic treatment have already been performed and their results are in the process of publication.

The safety and efficacy of Neuronox^® in aesthetic applications were presented at the 22nd World Congress of Dermatology in 2011. A total of 49 women with symmetric crow’s feet were enrolled in a double-blind, randomized, intraindividual controlled study. Patients’ crow’s feet were treated with 12 units of Botox^® on one side and with same dose of Neuronox^® on the other side. Clinical improvement was assessed by blinded investigators based on photographs taken at 1, 4, and 12 weeks post-treatment on a four point grading scale from poor to excellent; at all timepoints, there was no significant difference between two treatments (p > 0.05). At 4 weeks post-treatment, 95.7% of the sides treated with Botox^® and 100% of those treated with Neuronox^® demonstrated a good or excellent result, with 42.6% of either group having an ‘excellent’ result. Also, both products were well tolerated without any clinically significant treatment-related adverse events.

In another clinical trial, Neuronox^® was also directly compared with Botox^® at 1 : 1 dose ratio for the treatment of glabellar lines in a double-blind, randomized Phase III study. A total of 314 patients aged 20 to 65 with moderate to severe glabellar lines were randomly treated with 20 units of Neuronox^® or Botox^® and assessed by blinded investigators. Neuronox^® was again proven to be non-inferior to Botox^® without any significant difference in any of the efficacy end-points, including live assessment at maximum frown and at rest, photographic assessment, and the subject’s self-assessment of improvement and satisfaction for up to 16 weeks. Both products were well tolerated (publication in progress). Interestingly, the response rates at maximum frown at 4 weeks were higher in this study (93.8% in the Neuronox^® group and 94.6% in the Botox^® group) than those conducted in the USA (76.7% and 83.7% with Botox^®) and comparable with those from China and Japan (88.6%, 95.1%, and 94.1% with Botox^®). All these studies had the same timepoint, method of assessment, and the definition of ‘responder’, but different demographics (Asian versus Caucasian).

Based on these clinical data, we could conclude that the efficacy and safety of Neuronox^® are comparable with those of Botox^® not only in the treatment of blepharospasm and muscle spasticity in cerebral palsy, but also in the treatment of wrinkles such as glabellar lines and crow’s feet.

Reconstitution and handling

Neuronox^® is supplied as a single-use vial containing 50, 100, or 200 units of BoNT-A complex. The package insert for Neuronox^® recommends reconstituting it with non-preserved 0.9% sodium chloride injection. In a 2009 survey of 500 Korean dermatologists and plastic surgeons, 49.8% of responders dilute a 100 unit vial with 2.5 mL, yielding 4 units per 0.1mL, and 20.6% of responders dilute a 100 units vial with 2 mL yielding 5 units per 0.1 mL. Unreconstituted Neuronox^®

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