Bruce A C Cree1, Jeffrey L Bennett2, Ho Jin Kim3, Brian G Weinshenker4, Sean J Pittock4, Dean M Wingerchuk5, Kazuo Fujihara6, Friedemann Paul7, Gary R Cutter8, Romain Marignier9, Ari J Green10, Orhan Aktas11, Hans-Peter Hartung11, Fred D Lublin12, Jorn Drappa13, Gerard Barron14, Soraya Madani13, John N Ratchford13, Dewei She13, Daniel Cimbora13, Eliezer Katz13. 1. UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. Electronic address: bruce.cree@ucsf.edu. 2. School of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA. 3. Research Institute and Hospital of National Cancer Center, Seoul, South Korea. 4. Mayo Clinic, Rochester, MN, USA. 5. Mayo Clinic, Scottsdale, AZ, USA. 6. Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan; Multiple Sclerosis and Neuromyelitis Optica Center, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan. 7. Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine, Berlin, Germany; Charité-Universitätsmedizin Berlin, Berlin, Germany. 8. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA. 9. Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Lyon University Hospital, Lyon, France. 10. UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, USA; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA. 11. Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 12. Icahn School of Medicine at Mount Sinai, New York, NY, USA. 13. Viela Bio, Gaithersburg, MD, USA. 14. MedImmune, Cambridge, UK.
Abstract
BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS:Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receivinginebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receivinginebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receivinginebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receivinginebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.
RCT Entities:
BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.
Authors: Wajih Bukhari; Laura Clarke; Cullen O'Gorman; Elham Khalilidehkordi; Simon Arnett; Kerri M Prain; Mark Woodhall; Roger Silvestrini; Christine S Bundell; Sudarshini Ramanathan; David Abernethy; Sandeep Bhuta; Stefan Blum; Mike Boggild; Karyn Boundy; Bruce J Brew; Wallace Brownlee; Helmut Butzkueven; William M Carroll; Celia Chen; Alan Coulthard; Russell C Dale; Chandi Das; Keith Dear; Marzena J Fabis-Pedrini; David Fulcher; David Gillis; Simon Hawke; Robert Heard; Andrew P D Henderson; Saman Heshmat; Suzanne Hodgkinson; Sofia Jimenez-Sanchez; Trevor J Kilpatrick; John King; Chris Kneebone; Andrew J Kornberg; Jeannette Lechner-Scott; Ming-Wei Lin; Christopher Lynch; Richard A L Macdonnell; Deborah F Mason; Pamela A McCombe; Jennifer Pereira; John D Pollard; Stephen W Reddel; Cameron Shaw; Judith Spies; James Stankovich; Ian Sutton; Steve Vucic; Michael Walsh; Richard C Wong; Eppie M Yiu; Michael H Barnett; Allan G Kermode; Mark P Marriott; John Parratt; Mark Slee; Bruce V Taylor; Ernest Willoughby; Robert J Wilson; Fabienne Brilot; Angela Vincent; Patrick Waters; Simon A Broadley Journal: J Neurol Date: 2020-01-31 Impact factor: 4.849
Authors: Ruoyi Jiang; Miriam L Fichtner; Kenneth B Hoehn; Minh C Pham; Panos Stathopoulos; Richard J Nowak; Steven H Kleinstein; Kevin C O'Connor Journal: JCI Insight Date: 2020-07-23