Prabotulinum toxin A

Introduction

Prabotulinum toxin A is a 900 kDa botulinum toxin type A produced by Clostridium botulinum . Typical of this class of products, its basic mechanism of action involves cleavage of the synaptosomal-associated protein, SNAP25, thereby preventing degranulation of acetylcholine from the presynaptic nerve terminal and resulting in a relaxed muscle paralysis. Prabotulinum toxin A was licensed to Evolus (Newport Beach, CA) from Daewoong (Daewoong Pharmaceutical Co. Ltd., South Korea) for clinical development and distribution in numerous countries including the United States (US), Canada, the United Kingdom (UK), and European Union (EU). Prabotulinum toxin A (Jeuveau) was approved by the US Federal Drug Administration (FDA) in February 2019 as an intramuscular injection for temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients. Prabotulinum toxin A has since been similarly approved in Canada, the UK and the 30 countries of the EU, where it is known by the trade name Nuceiva. The final vacuum-dried formulation of 100 units (U) also contains the excipients human serum albumin and sodium chloride.

Manufacturing

Prabotulinum toxin A was originally manufactured using a freeze-drying process to remove water from the vial. However, this process denatured the protein complex, possibly as a result of ice crystal formation. To compensate, a substantial overage of the botulinum toxin was needed to yield 100 U of activity in the end product. To improve the purity, the process was changed to vacuum-drying which required little-to-no overage because there was essentially little-to-no degradation of the botulinum toxin. High purity was also achieved by effective isolation of the drug substance followed by purification using multi-column ion exchange chromatography.

As evident from antibody testing conducted in the four US glabellar line clinical trials—one conducted with the earlier freeze-dried product, and three conducted with the vacuum-dried product, significantly decreasing the protein load by employing a vacuum-drying process also seemed to confer immunological benefits. Specifically, of the 1087 treatments administered with the freeze-dried product, two cases of antibody formation were observed because of exposure to that product whereas, no cases were observed following any of the 2231 treatments administered with the final FDA-approved commercial vacuum-dried product.