Efficacy and safety of two incobotulinumtoxinA injection intervals in cervical dystonia patients with inadequate benefit from standard injection intervals of botulinum toxin: Phase 4, open-label, randomized, noninferiority study

Abstract

IntroductionSome patients with cervical dystonia (CD) receiving long-term botulinum neurotoxin (BoNT) therapy report early waning of treatment benefit before the typical 12-week reinjection interval.

Methods: This phase 4, open-label, randomized, noninferiority study (CD Flex; NCT01486264) compared 2 incobotulinumtoxinA injection schedules (Short Flex: 8 ± 2 weeks; Long Flex: 14 ± 2 weeks) in CD patients. Previous BoNT-responsive subjects who reported acceptable clinical benefit lasting < 10 weeks were recruited. Efficacy and safety were evaluated after 8 injection cycles. The primary endpoint was change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 4 weeks after the eighth injection. Secondary endpoints included TWSTRS total and subscale scores. Immunogenicity was assessed in a subset of patients.

Results: Two hundred eighty-two CD patients were randomized and treated (Short Flex, N = 142; Long Flex, N = 140), and 207 completed the study. Significant improvements in TWSTRS severity from study baseline to 4 weeks after cycle 8 were observed in both the Short Flex (4.1 points; P < 0.0001) and Long Flex (2.4 points; P = 0.002) groups; Short Flex was noninferior to Long Flex (LS mean difference = 1.4 points; 95% CI = [-2.9, 0.1] < Δ = 2.0). Key secondary endpoints favored Short Flex intervals. Adverse events (AEs) were comparable between groups. There was no secondary loss of treatment effect.

Conclusion: Injection cycles < 10 weeks for incobotulinumtoxinA are effective (and noninferior to longer intervals) for treating CD patients with early waning of clinical benefit. Shorter injection intervals did not increase AEs or lead to loss of treatment effect.

Keywords: BoNT; Botulinum toxin; Cervical dystonia; IncobotulinumtoxinA; Movement disorders.

Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Disclosures: Cynthia Comella serves on the editorial board of Clinical Neuropharmacology and Sleep Medicine. She has received compensation/honoraria for services as a consultant or an advisory committee member for Acadia Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, AEON Biopharma, Allergan, Ipsen Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Merz Pharmaceuticals, Neurocrine Biosciences, Revance Therapeutics, and Sunovion Pharmaceuticals. She receives royalties from Wolters Kluwer. Robert Hauser has received consulting fees from AbbVie, Acadia, Acorda, Adamas, Alterity, Amneal, Aptinyx, Britannia, Cerevance, Curium Pharma, Enterin, Inhibikase, Jazz, KeiferRx, Kyowa Kirin, Lundbeck A/S, Merck, Merz, Neurocrine Biosciences, Novus, Pharma Two B, Pharmather, Revance Therapeutics, Roche, Sage Therapeutics, Scion NeuroStim, Sio Gene Therapies, Sunovion, Supernus, Tolmar, US WorldMeds, and Vivifi Biotech and has received speaker fees from AbbVie, Acorda, Adamas, Amneal, Kyowa Kirin, Neurocrine Biosciences, and Sunovion. He holds stock in Axial Biotherapeutics and Inhibikase. His institution, University of South Florida, received research fees from AbbVie, Axovant Sciences, Biogen, Bukwang Pharmaceuticals, Cavion, Centogene, Cerevance, Cerevel Therapeutics, Cynapsus Therapeutics, Enterin, F. Hoffmann-La Roche, Genentech, Global Kinetics Corporation, Impax Specialty Pharma, Intec Pharma, Integrative Research Laboratories Sweden AB, Jazz Pharmaceuticals, MJFF, Neuraly, NeuroDerm, Neurocrine Biosciences, Northwestern University, Pfizer, Pharma Two B, Revance Therapeutics, Sanofi US Services, Sun Pharma Advanced Research Company, Sunovion Pharmaceuticals, and UCB Biopharma SPRL. Stuart Isaacson has received honoraria for CME for, was a consultant for, received research grants from, and/or was a promotional speaker on behalf of Abbvie, Allergan, Ipsen, Merz, Revance, Supernus, and US World Meds. Daniel Truong has received research funding from Abbvie, Acorda, Aeon, Auspex, Biogen, Bukwang, Cerevel, Cynapsus, Daiichi Sankyo Pharma, Eli Lilly, Enterin, Ipsen, Kyowa, Lundbeck, Merz, National Institute of Neurological Disorders and Stroke, Neurocrine, Neuroderm, Parkinson’s Foundation, Prilenia, Revance, and Sunovion. He has received honoraria for consulting and speaker activities from Acorda, Neurocrine, TEVA, an US Worldmed. Odinachi Oguh is a paid speaker and consultant for Sunovion Pharmaceuticals. Jennifer Hui is an advisory board member for Acorda, serves as a consultant for Sunovion, and receives grant support from Roche. Eric Molho is on the speakers bureau for Neurocrine Biosciences; received research funding from Amneal Pharmaceuticals, Biohaven Pharmaceuticals, Cerevel Therapeutics, CHDI/HSG, and Enterin; and received educational grants from AbbVie and Merz Pharmaceuticals. Matthew Brodsky has no conflicts of interest to disclose. Erin Furr-Stimming receives research funding from Cures within Reach, HDSA, Neurocrine, Prilenia, Roche/Genetech, and Uniqure; has consulted for Teva; and is on the speakers bureau for Sunovion; none of these are related to Xeomin or conflict with work being presented. Georg Comes and Michael Hast and are employees of Merz Pharmaceuticals. David Charles received income from Alliance for Patient Access, Merz, Newronika, Revance, and Supernus for consulting services. His institution, Vanderbilt University Medical Center, receives income from grants or contracts with Abbott, AbbVie, Aeon, Boston Scientific, Impax, Intec, Ipsen, Lundbeck, Medtronic, Merz, Novartis, Pharma Two B, and Supernus for research or educational programs that he has led.

© 2022 Published by Elsevier Ltd.

Figures

Fig. 1

(A) Primary efficacy outcome of change in blinded-rater assessment of TWSTRS severity subscale score from baseline to 4 weeks after the eighth injection in the Short Flex and Long Flex groups reported for all subjects in PPS. PPS included subjects from FAS who were responsive to the UBI at the 4-week control visit with no major protocol deviations. (B) Sensitivity analysis of change in blinded-rater assessment of TWSTRS severity subscale score from baseline to 4 weeks after the eighth injection in the Short Flex and Long Flex groups reported for all subjects in FAS. FAS subset included randomized subjects who received at least 1 injection and for whom a blinded-rater TWSTRS severity value was available at the baseline injection visit and the control visit 4 weeks after the eighth injection. Error bars represent standard error. FAS, full analysis set; LS, least squares; PPS, per protocol set; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; UBI, unilateral brow injection.