Gavin Giovannoni1, Ludwig Kappos2, Ralf Gold3, Bhupendra O Khatri4, Krzysztof Selmaj5, Kimberly Umans6, Steven J Greenberg7, Marianne Sweetser8, Jacob Elkins9, Peter McCroskery10. 1. Queen Mary University of London, Blizard Institute, Barts and the London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK. Electronic address: g.giovannoni@qmul.ac.uk. 2. Neurology, Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. Electronic address: ludwig.kappos@usb.ch. 3. Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Gudrunstraße 56, 44791 Bochum, Germany. Electronic address: Ralf.Gold@ruhr-uni-bochum.de. 4. Center for Neurological Disorders and The Regional Multiple Sclerosis Center, Wheaton Franciscan Health Care St. Francis Hospital, 3237S 16th Street, Milwaukee, WI 53215, USA. Electronic address: bokhatri@aol.com. 5. Department of Neurology, Medical University of Lodz, ul. Kopcinskiego 22, 90-153 Lodz, Poland. Electronic address: kselmaj@afazja.am.lodz.pl. 6. Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: kim.umans@biogen.com. 7. AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: steven.greenberg@abbvie.com. 8. Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: msweetser@alnylam.com. 9. Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: jake.elkins@biogen.com. 10. Biogen, 225 Binney Street, Cambridge, MA 02142, USA. Electronic address: peter.mccroskery@biogen.com.
Abstract
BACKGROUND:Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. OBJECTIVE: Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. METHODS: Patients treated with at least one dose of subcutaneous daclizumab 150mg or 300mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. RESULTS: This analysis included 2236 patients with 5214 patient-years of exposure todaclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. CONCLUSION: This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time.
RCT Entities:
BACKGROUND:Daclizumab has been evaluated in multicentre, randomised, double-blind studies for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). Safety and tolerability are key considerations in MS treatment selection, as they influence adherence to medication. OBJECTIVE: Evaluate the safety of daclizumab in patients with RRMS from an integrated analysis of six clinical studies. METHODS:Patients treated with at least one dose of subcutaneous daclizumab 150mg or 300mg monthly in three completed and three ongoing clinical studies were included in this integrated analysis. Cumulative incidence of treatment-emergent adverse events (AEs) was the primary endpoint. RESULTS: This analysis included 2236 patients with 5214 patient-years of exposure to daclizumab. The cumulative incidence of any AE was 84% and of any serious AE excluding MS relapse was 16%. The incidences of AEs when evaluated by 6-month intervals remained stable over the 6.5 years of maximum follow-up. Most AEs were mild or moderate in severity. An important safety concern associated with daclizumab therapy involved hepatic AEs (16%) and serum transaminase elevations at least three times the upper limit of normal (10%), most of which were asymptomatic, self-limiting, and non-recurring. Cumulative incidences of cutaneous, infectious, and gastrointestinal AEs were 33%, 59%, and 25%, respectively; most events either resolved spontaneously or were treated successfully with standard medical interventions and did not result in discontinuation of treatment. CONCLUSION: This integrated analysis demonstrates that treatment of RRMS with daclizumab for periods of up to 6.5 years is associated with an acceptable safety profile with no evidence of cumulative toxicity over time.
Authors: Moritz Förster; Patrick Küry; Orhan Aktas; Clemens Warnke; Joachim Havla; Reinhard Hohlfeld; Jan Mares; Hans-Peter Hartung; David Kremer Journal: Drug Saf Date: 2019-05 Impact factor: 5.606