Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis
Neurology. 2024-12-24; 103(12):
DOI: 10.1212/WNL.0000000000210049
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1. Neurology. 2024 Dec 24;103(12):e210049. doi: 10.1212/WNL.0000000000210049.
Epub 2024 Dec 3.
Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase
IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial.
Hartung HP(1), Benedict RHB(1), Berger T(1), Bermel RA(1), Brochet B(1), Carroll
WM(1), Freedman MS(1), Holmøy T(1), Karabudak R(1), Nos C(1), Patti F(1), Perrin
Ross A(1), Vanopdenbosch L(1), Vollmer T(1), Wuerfel J(1), Clinch S(1), Kadner
K(1), Kuenzel T(1), Kulyk I(1), Raposo C(1), Thanei GA(1), Killestein J(1).
Author information:
(1)From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and
Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany;
Brain and Mind Centre (H.-P.H.), University of Sydney, Australia; Department of
Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic; Department of
Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences,
University of Buffalo, NY; Department of Neurology (T.B.), Medical University of
Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health,
Austria; Mellen Center for MS (R.A.B.), Cleveland Clinic, OH; Neurocentre
Magendie INSERM (B.B.), Université de Bordeaux, France; Department of Neurology
(W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and
Translational Science, The University of Western Australia, Nedlands; Department
of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of
Ottawa, Ontario, Canada; Department of Neurology (T.H.), Akershus University
Hospital, Lørenskog; Institute of Clinical Medicine (T.H.), University of Oslo,
Norway; Department of Neurology (R.K.), Hacettepe University Faculty of
Medicine, Ankara, Turkey; Centre d’Esclerosi Mútiple de Catalunya (Cemcat)
(C.N.), Vall d’Hebron Hospital Universitari, Barcelona, Spain; Department of
Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia,
Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO
Policlinico G Rodolico, Italy; Loyola University Chicago (A.P.R.), IL;
Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium; Department
of Neurology (T.V.), University of Colorado School of Medicine, Aurora; Medical
Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering,
University of Basel; F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K.,
C.R., G.-A.T.), Basel, Switzerland; and Department of Neurology (J.K.), VU
University Medical Centre, Amsterdam, the Netherlands.
BACKGROUND AND OBJECTIVES: Early treatment of multiple sclerosis (MS) reduces
disease activity and the risk of long-term disease progression. Effectiveness of
ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are
lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a
first-line therapy in treatment-naive patients with recently diagnosed
relapsing-remitting MS (RRMS).
METHODS: ENSEMBLE was a prospective, 4-year, international, multicenter,
single-arm, open-label, phase IIIb study. Patients were treatment naive, aged
18-55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded
Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s)
or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months.
Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints
over 192 weeks were proportion of patients with no evidence of disease activity
(NEDA-3; defined as absence of relapses, 24-week confirmed disability
progression [CDP], and MRI measures, with prespecified MRI rebaselining at week
8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized
relapse rate (ARR), mean change in EDSS score from baseline, and safety.
Cognitive status, patient-reported outcomes, and serum neurofilament light chain
(NfL) were assessed. Descriptive analysis was performed on the
intention-to-treat population.
RESULTS: Baseline characteristics (N = 678) were consistent with early-stage
RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0
years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years;
mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients
had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no
relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at
week 192 was low (0.020, 95% CI 0.015-0.027). NfL levels were reduced to and
remained within the healthy donor range, by week 48 and week 192, respectively.
No new or unexpected safety signals were observed.
DISCUSSION: Disease activity based on clinical and MRI measures was absent in
most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE
study. Safety was consistent with the known profile of ocrelizumab. Although
this single-arm study was limited by lack of a parallel group for comparison of
outcome measures, the positive benefit-risk profile observed may provide
confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed
patients with early RMS.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that adult
patients with early-stage MS who were treatment naive maintained low disease
activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals
were detected.
TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT03085810; first
submitted March 16, 2017; first patient enrolled: March 27, 2017; available at
clinicaltrials.gov/ct2/show/NCT03085810.
DOI: 10.1212/WNL.0000000000210049
PMID: 39626127 [Indexed for MEDLINE]