Neutralizing Antibody Formation with OnabotulinumtoxinA (BOTOX®) Treatment from Global Registration Studies across Multiple Indications: A Meta-Analysis

Abstract

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy.

Keywords: aesthetics; bladder; blepharospasm; cervical dystonia; hyperhidrosis; migraine disorders; neurotoxins; overactive; spasticity; type A botulinum toxins.

Figure 1

Numbers within or above the circles reflect subject records available for neutralizing antibody evaluation at each treatment cycle (95% of subjects received 1–9 cycles) by approved indication, Indications are ordered by year of onabotulinumtoxinA approval, with approval year in parentheses. Circle sizes are proportional to the number of patient records indicated.

Figure 2

NAb status post-treatment and at study exit of subjects who were seronegative at baseline, by indication. Numbers refer to numbers of subjects. NAb, neutralizing antibody; NDO, neurogenic detrusor overactivity.

Figure 3

Jitter plot showing subjects who were NAb negative (top) and NAb positive (bottom) by dose and treatment cycle for each approved indication (≈95% of subjects received 1–9 treatment cycles; no subject was positive beyond treatment cycle 9).

Figure 4

Methodology to determine NAb formation in response to onabotulinumtoxinA treatment based on individual subject scenarios for baseline vs. post-treatment NAb results. Abbreviations—NAb, neutralizing antibody; OnabotA, onabotulinumtoxinA.