Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis

Abstract

IncobotulinumtoxinA, a pure botulinumtoxinA formulation, is free of accessory proteins. This analysis provides pooled safety data from phase 3 trials of children/adolescents (2-17 years), investigating incobotulinumtoxinA for the treatment of spasticity associated with cerebral palsy (at doses ≤20 U/kg (max. 500 U) per injection cycle (IC) for ≤6 ICs; three trials) or sialorrhea associated with neurologic disorders (at total doses of 20-75 U per IC for ≤4 ICs; one trial) for ≤96 weeks. Safety endpoints included the incidences of different types of treatment-emergent adverse events (TEAEs) and immunogenicity. IncobotulinumtoxinA dose groups were combined. Of 1159 patients (mean age 7.3 years, 60.4% males) treated with incobotulinumtoxinA, 3.9% experienced treatment-related TEAEs, with the most common being injection site reactions (1.3%) (both indications), muscular weakness (0.7%) (spasticity), and dysphagia (0.2%) (sialorrhea). Two patients (0.2%) experienced a treatment-related treatment-emergent serious adverse event, and 0.3% discontinued the study due to treatment-related TEAEs. No botulinumtoxinA-naïve patients developed neutralizing antibodies (NAbs) after incobotulinumtoxinA. All children/adolescents with known pre-treatment status and testing positive for Nabs at final visit (n = 7) were previously treated with a botulinumtoxinA other than incobotulinumtoxinA. IncobotulinumtoxinA was shown to be safe, with very few treatment-related TEAEs in a large, diverse cohort of children/adolescents with chronic conditions requiring long-term treatment and was without new NAb formation in treatment-naïve patients.

Trial registration: ClinicalTrials.gov NCT01893411 NCT01905683 NCT02002884 NCT02270736.

Keywords: all movement disorders; all pediatric; antibodies; botulinum toxin; immunogenicity; incobotulinumtoxinA; muscle spasticity; safety; sialorrhea.

Conflict of interest statement

Steffen Berweck has received consultant fees from Ipsen Pharma and Merz Therapeutics and speaker fees from Ipsen Pharma, Pharm Allergan, and Merz Therapeutics. Marta Banach has served as a consultant and speaker and participated in an advisory board for Merz Pharmaceuticals and has served as a speaker for Allergan, Ipsen, and Kedrion. Deborah Gaebler-Spira has served as a consultant for Teva and Kashiva. Henry G. Chambers serves as a consultant for Orthopediatrics Corp and Allergan Corporation. A. Sebastian Schroeder has received speaker’s honoraria from and participated in advisory boards for Allergan PLC, Ipsen Biopharmaceuticals, and Merz Therapeutics. Thorin L. Geister, Michael Althaus, Angelika Hanschmann, and Matteo Vacchelli are all employees of Merz Therapeutics. Michaela Bonfert has received research grants from the HABA Foundation, the Deutsche Rentenversicherung, the Deutsche Migräne und Kopfschmerzgesellschaft, the European Research Council, ERA-NET Neuron, CSL Behring, and the ZNS-Hannelore Kohl Foundation and a research scholarship of the Bavarian Gender Equality Grant of the Free State of Bavaria, Germany. Edward Dabrowski has participated in an advisory board and speaker bureau for Ipsen Biopharmaceuticals. Florian Heinen has received speaker’s honoraria from Allergan PLC, Desitin, Ipsen Biopharmaceuticals, Merz Therapeutics, and Novartis and unrestricted educational grants from Allergan and Merz Therapeutics.

Figures

Figure 1

The incidence of TEAEs by IC for pediatric patients with spasticity or sialorrhea treated with incobotulinumtoxinA a. a All patients with spasticity were enrolled in TIM (Treatment with IncobotulinumtoxinA in Movement) [17], TIMO (Treatment with IncobotulinumtoxinA in Movement Open-label) [18], or XARA (incobotulinumtoXinA in aRm treatment in cerebral pAlsy) [19], and patients with sialorrhea were enrolled in SIPEXI (Sialorrhea Pediatric Xeomin Investigation) [20]. IC, injection cycle; TEAE, treatment-emergent adverse event; TEAESI, treatment-emergent adverse event of special interest (potentially indicative of toxin spread); TESAE, treatment-emergent serious adverse event; TR, treatment-related.

Figure 2

The incidence of TEAEs by IC for pediatric patients with spasticity treated with incobotulinumtoxinA a. a All patients were enrolled in TIM (Treatment with IncobotulinumtoxinA in Movement) [17], TIMO (Treatment with IncobotulinumtoxinA in Movement Open-label) [18], or XARA (incobotulinumtoXinA in aRm treatment in cerebral pAlsy) [19]. IC, injection cycle; TEAE, treatment-emergent adverse event; TEAESI, treatment-emergent adverse event of special interest (potentially indicative of toxin spread); TESAE, treatment-emergent serious adverse event; TR, treatment-related.

Figure 3

The incidence of TEAEs by IC for pediatric patients with sialorrhea treated with incobotulinumtoxinA a. a All patients enrolled in SIPEXI (Sialorrhea Pediatric Xeomin Investigation) [20]. IC, injection cycle; TEAE, treatment-emergent adverse event; TEAESI, treatment-emergent adverse event of special interest (potentially indicative of toxin spread); TESAE, treatment-emergent serious adverse event; TR, treatment-related.

Figure 4

Simplified overview of the study designs of the four phase 3 pediatric studies TIM, TIMO, XARA, and SIPEXI a. a Full methodologic details can be found in: TIM [17], TIMO [18], XARA [19], and SIPEXI [20]. b Maximum duration of treatment was 96 weeks for those from the TIM study who entered TIMO. AB: For TIM patients who did not progress to TIMO, AB was performed at the SV and the EOS visit (e.g., after two ICs). For those enrolled in TIM and who progressed to TIMO, AB was performed at the TIM SV and the TIMO EOS visit (e.g., after up to six ICs). For patients newly enrolled in TIMO and for patients in XARA and SIPEXI, AB was performed at the SV and the EOS visit (e.g., after four ICs). AB was restricted to patients weighing ≥21 kg body weight in the spasticity studies and ≥30 kg body weight in the sialorrhea study to reduce the burden of further blood sample requirements on smaller, younger patients. AB, antibody testing; BW, body weight; EOS, end of study; IC, injection cycle; LL, lower limb; MP, main period; OLEX, open-label extension; SIPEXI, Sialorrhea Pediatric Xeomin Investigation; SV, screening visit; TIM, Treatment with IncobotulinumtoxinA in Movement; TIMO, Treatment with IncobotulinumtoxinA in Movement Open-label; U, unit; UL, upper limb; XARA, incobotulinumtoXinA in aRm treatment in cerebral pAlsy.