The development of toxin neutralising antibodies with botulinum toxin type A (BoNTA) treatment

Background: Botulinum toxin type A (BoNTA: BOTOX®, Allergan, Inc.) has been studied in the treatment of a variety of disorders such as cervical dystonia (CD), chronic headache, and lower or upper limb spasticity. The development of neutralizing antibodies that interfere with clinical effectiveness is a risk of repeated exposure to BoNTA and is influenced by the dose, the treatment interval, the protein exposure, and proper injection technique.

Objective: To assess the rate of neutralizing antibody formation with the current formulation of intramuscular injection of BoNTA in previously naive patients.

Methods: Antibody samples were obtained from clinical studies in which patients were treated with BoNTA for CD, headache, or post-stroke spasticity. CD patients (n=326) received 1–15 treatments of BoNTA (mean per treatment: 187.3U; range per treatment: 20–500U; maximum total per patient: 4210U); chronic headache patients (n=356) received 3 treatments (mean: 157U; range 75–260U; maximum: 780U); and post-stroke spasticity patients (n=247) received 1–4 treatments (mean: 241U; range 100–360U; maximum: 960U). In the chronic headache trials, only the patients that completed all 3 treatment cycles and had analyzable serum samples were included in this analysis. The presence of neutralizing antibodies to BoNTA was assessed using the mouse protection assay (MPA). The MPA detects the presence of specific antibodies that neutralize the biological activity of BoNTA. The assay is performed by mixing patient serum with test toxin, and injecting 4 mice. The MPA is considered negative if 3 or more mice die, positive if 3 or more mice live, and inconclusive if 2 mice die.

Results: Of the 929 patients treated, 880 had analyzable samples, of which only 5 patients tested positive on the MPA (<1%). Of the 5 patients with a positive MPA result, 4 were CD patients, with a maximum exposure to BoNTA ranging from 1200 to 3100U. The other patient with a positive MPA result was a spasticity patient who received one treatment with BoNTA 200U. Only the spasticity patient did not demonstrate clinical responsiveness at the time of reporting the positive MPA.

Conclusion: The rate of antibody formation was less than 1% in patients who received repeated BoNTA intramuscular injections with the current BoNTA formulation used in these studies.