An Evaluation of Neutralizing Antibody Induction During Treatment of Glabellar Lines with a New US Formulation of Botulinum Neurotoxin Type A

Abstract

The induction of neutralizing antibodies during the aesthetic application of botulinum neurotoxin type A is rare, but of potential clinical concern. Phase III studies of a new US formulation of botulinum neurotoxin type A, Dysport (BoNTA-ABO [abobotulinumtoxinA]; Medicis Aesthetics, Scottsdale, AZ), have not identified any cases of neutralizing antibody formation during the treatment of glabellar lines in patients who received up to nine treatments. To provide an in-depth analysis of the potential for induction of neutralizing antibodies in the study population enrolled in phase III trials of BoNTA-ABO in the treatment of glabellar lines. First and last available serum samples from patients in the BoNTA-ABO Glabellar Lines Development Program were screened for BoNTA-ABO antibodies with a radioimmunoprecipitation assay (RIPA), followed by a confirmatory competitive assay (RIPA-C). Confirmed RIPA-C-positive samples were further evaluated for the presence of neutralizing antibodies using a mouse protection assay (MPA), a highly specific bioassay for neutralizing antibodies. We conducted safety and efficacy evaluations, including day 30 responder rate (a rating of no or mild glabellar lines) and duration of response in the last treatment cycle. Of 1554 patients who received at least one BoNTA-ABO treatment (10 units at five injection points, for a total dose of 50 units/treatment; range one to nine treatments), five (0.32%) were antibody positive on the RIPA-C assay-two at baseline and three at the last treatment cycle. None of the RIPA-C-positive samples tested positive for neutralizing antibodies upon further evaluation using the highly specific MPA. Of note, the RIPA-C-positive group had a responder rate of 100% and a mean response of 103.3 days, while the RIPA-C-negative group had a responder rate of 90% and a mean response of 89.4 days. The safety of BoNTA-ABO did not appear to be altered in the RIPA-C-positive group. At the dose and treatment interval used in the correction of glabellar lines, induction of neutralizing antibodies to BoNTA-ABO was not observed. None of the five samples that initially gave positive results in a RIPA-C assay were positive when further evaluated using the MPA. Clinically, RIPA-C-positive status did not correlate with any reduction in efficacy or an altered safety profile, although the small numbers prevent definitive conclusions. These data suggest that the five RIPA-C-positive samples represented false positives.