Injectable DaxibotulinumtoxinA in Cervical Dystonia: A Phase 2 Dose‐Escalation Multicenter Study

Abstract

BackgroundInjectable daxibotulinumtoxinA (an investigational botulinum toxin, RT002) may offer a more prolonged duration of response—and therefore less frequent dosing—than onabotulinumtoxinA.ObjectivesTo perform a phase 2, open‐label, dose‐escalation study to assess the efficacy and safety of daxibotulinumtoxinA in cervical dystonia.MethodsSubjects with moderate‐to‐severe isolated cervical dystonia were enrolled in sequential cohorts to receive a single open‐label, intramuscular dose of injectable daxibotulinumtoxinA of up to 200 U (n = 12), 200–300 U (n = 12), or 300–450 U (n = 13; https://clinicaltrials.gov identifier NCT02706795).ResultsOverall, 33/37 enrollees completed the trial. DaxibotulinumtoxinA was associated with mean reductions in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)‐Total score of 16.8 (38%) at week 4, 21.3 (50%) at week 6, and 12.8 (30%) at week 24. The proportion of subjects who were responders (achieved ≥ 20% reduction in TWSTRS‐Total score) was 94% at week 6 and 68% at week 24. The median duration of response (time until > 20% of the improvement in TWSTRS‐Total score achieved at week 4 was no longer retained or re‐treatment was needed) was 25.3 weeks (95% CI, 20.14–26.14 weeks). There were no serious adverse events and there was no apparent dose‐related increase in the incidence of adverse events. The most common treatment‐related adverse events were dysphagia (14%) and injection site erythema (8%).ConclusionsPreliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450 U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia. Further studies involving larger numbers of patients are now warranted.

The mechanisms of action and use of botulinum neurotoxin type A in aesthetics: Key Clinical Postulates II

“…It uses the same A1 toxin subtype as OnabotulinumtoxinA, AbobotulinumtoxinA, IncobotulinumtoxinA, and PrabotulinumtoxinA but adds a peptide excipient (RTP004) that binds to the neurotoxin in order to stabilize and prevent aggregation of the toxin in solution 3 . The peptide is made up of two protein transduction domains consisting of a lysine chain that provides a strong electrostatic bond for the novel toxin to bind 3,60 . The end result is more “active” toxin available for binding upon injection and thus a higher molecular potency.…”

Immunogenicity Associated with Botulinum Toxin Treatment

“…This peptide is presumably designed to reduce diffusion of the neurotoxin and consequently increase its duration of effect. A phase 2 open-label trial of daxibotulinumtoxinA in 33 patients with CD noted a mean duration of effect of 25.3 weeks, longer than typical effect durations of other BoNT-A formulations [34]. A similar prolonged effect was noted in another phase 2 trial examining its use in the treatment of glabellar lines [39].…”

“…These associations of core neurotoxin and NAPs are mixed with excipients, which vary among different brands, but include albumin, sucrose, lactose, sodium chloride, and disodium succinate [24]. DaxibotulinumtoxinA, a new formulation currently in development has a unique peptide excipient (described further below) [34].…”

“…Overall, BoNT-A has greater motor effects while BoNT-B has greater autonomic effects associated, for example, with dryness of the mouth due to reduced salivary secretions [24,38]. DaxibotulinumtoxinA is composed of a purified core neurotoxin without any NAPs (similar to incobotulinumtoxinA) and a stabilizing excipient peptide that binds to the neurotoxin [34]. This peptide is presumably designed to reduce diffusion of the neurotoxin and consequently increase its duration of effect.…”

Reply to Comment on Re-Visiting Immunogenicity Associated with Botulinum Toxin Treatment. Toxins 2019, 11, 491

“…Although this view is frequently expressed by patients treated with BoNT, we certainly do not endorse or advocate for "booster" injections, which in the past have been associated with high frequency of immunoresistance [1]. Most studies examining the effects and safety of shorter inter-dose intervals used incobotulinumtoxinA [12][13][14], but more comparative data are needed before concluding that one product or another is associated with less immunogenicity or longer duration of action [15].…”