Comparative evaluation of the potency and antigenicity of two distinct BoNT/A-derived formulations

Abstract

IncobotulinumtoxinA (Xeomin^®) and onabotulinumtoxinA (BOTOX^®) are unique botulinum neurotoxin type A (BoNT/A)-derived drugs. IncobotulinumtoxinA utilizes the naked 150 kDa holotoxin portion of BoNT/A, whereas onabotulinumtoxinA uses the complete native 900 kDa complex as drug substance. On the basis of purportedly similar pharmacological characteristics, these formulations were evaluated for potency by LD₅₀ and mouse Digit Abduction Score (DAS) bioassays. DAS was also used to assess antigenicity. Full-range DAS dose–response profiles were achieved with four lots of each product, with similar observations between lots for a given product. Between products, however, the mean DAS potency of incobotulinumtoxinA (ED₅₀ range 7.0–10.2 U/kg) was significantly lower than that of onabotulinumtoxinA (ED₅₀ range 4.4–6.4 U/kg), consistent with lower measured potencies in the LD₅₀ assay for incobotulinumtoxinA (potency range 62–82 U). In assessments of DAS duration of effect at similar unit doses, the observed lower potency of incobotulinumtoxinA translated into decreased peak efficacy and dose effect over time (i.e. shorter duration). In contrast, at equi-efficacious doses yielding near-maximal DAS responses, both toxin formulations were uniformly inhibited in a statistically significant manner when preincubated with rabbit-derived, onabotulinumtoxinA-neutralizing antibodies, supporting the position that inhibition of 150 kDa holotoxin serves as the common basis for neutralization and, therefore, incobotulinumtoxinA would not be expected to be effective in onabotulinumtoxinA-immunoresistant subjects (and vice versa). Further, with lower lot-to-lot relative potency, incobotulinumtoxinA is not dose-equivalent or interchangeable with onabotulinumtoxinA, suggesting that various aspects of drug product formulation may influence observed pharmacology.