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Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis - results of the placebo-controlled, double-blind, Phase III ORATORIO study
Author(s): ,
X. Montalban
Affiliations:
Hospital Vall d'Hebron University, Barcelona, Spain
,
B. Hemmer
Affiliations:
Technische Universität München; Munich Cluster for Systems Neurology (SyNergy) (B.H.), Munich, Germany
,
K. Rammohan
Affiliations:
University of Miami, Miami, FL, United States
,
G. Giovannoni
Affiliations:
Queen Mary University of London, London, United Kingdom
,
J. de Seze
Affiliations:
University Hospital of Strasbourg, Strasbourg, France
,
A. Bar-Or
Affiliations:
McGill University
,
D.L. Arnold
Affiliations:
McGill University; NeuroRx Research, Montreal, QC, Canada
,
A. Sauter
Affiliations:
F. Hoffmann-La Roche Ltd., Basel, Switzerland
,
A. Kakarieka
Affiliations:
F. Hoffmann-La Roche Ltd., Basel, Switzerland
,
D. Masterman
Affiliations:
Genentech Inc., San Francisco, CA
,
P. Chin
Affiliations:
Genentech Inc., San Francisco, CA
,
H. Garren
Affiliations:
F. Hoffmann-La Roche Ltd., Basel, Switzerland
,
J. Wolinsky
Affiliations:
University of Texas Health Science Center at Houston, Houston, TX, United States
on behalf of the ORATORIO Clinical Investigators
on behalf of the ORATORIO Clinical Investigators
Affiliations:
ECTRIMS Online Library. Meca-Lallana V. Oct 10, 2015; 116701
Prof. Virginia Meca-Lallana
Prof. Virginia Meca-Lallana
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Abstract: 228

Type: Oral LB

Abstract Category: Invited / Oral LB / Poster LB

Background: Primary progressive multiple sclerosis (PPMS) accounts for 10-15% of the MS population. There is currently no approved disease-modifying treatment for PPMS. B cells are believed to contribute to the pathogenesis of MS, including PPMS. Ocrelizumab (OCR) is a recombinant humanised monoclonal antibody that selectively targets CD20+ B cells.

Objectives:
ORATORIO is a Phase III, multicentre, randomised, double-blind, placebo-controlled study aiming to assess the efficacy and safety of OCR in patients with PPMS (NCT01194570).

Methods
: Patients were randomised (2:1) to receive OCR 600 mg (given as two 300 mg intravenous infusions 14 days apart) or matching placebo every 24 weeks for at least 120 weeks or until approximately 253 three-month confirmed disability progression events occurred. Eligibility criteria included an age of 18-55 years, a diagnosis of PPMS (2005 revised McDonald criteria); Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at screening; disease duration (since MS symptoms) of < 15 years in patients with an EDSS score of > 5.0 at screening and < 10 years in patients with an EDSS score of ≤ 5.0 at screening; and documented evidence of elevated immunoglobulin index and/or presence of oligoclonal bands within the CSF. The primary endpoint is time to onset of confirmed disability progression, defined as a ≥ 12-week sustained increase in EDSS score.

Results: Overall, 732 patients were randomised at 183 sites. Mean age at baseline was 44.6 years; 49.3% of patients were female and 94.1% were white. Mean (standard deviation, SD) baseline EDSS score was 4.70 (1.17); mean (SD) duration since MS symptom onset was 6.48 (3.89) years; and mean (SD) duration since PPMS diagnosis was 2.82 (3.22) years. The number of patients untreated with any MS medication in the prior 2 years was 656 (89.6%). At baseline, 26.4% of patients had gadolinium-enhancing (Gd+) T1 lesions; mean (SD) number of Gd+ T1 lesions was 1.0 (4.31); median (min-max) volume of T2 lesions was 6.96 (0-90.3) cm3; and mean (SD) normalised brain volume was 1464.99 (85.96) cm3 on brain magnetic resonance imaging.

Conclusions: The ORATORIO baseline characteristics are consistent with disease characteristics of a PPMS population. As the primary endpoint is an event-driven analysis, the treatment period will be extended until approximately 253 three-month confirmed disability progression events have occurred. The results from this study will be presented after this target is reached.

Disclosure:

Research funded by F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, Merck Serono, Genentech Inc., Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, GSK, F. Hoffmann-La Roche Ltd., Almirall, NMSS and MSIF; he is also Editor for Clinical Cases for MSJ.

Bernhard Hemmer has served on scientific advisory boards for F. Hoffmann-La Roche Ltd., Novartis, Bayer Schering, Merck Serono, Biogen Idec, GSK, Chugai Pharmaceuticals, Micromet, Genentech Inc. and Genzyme Corporation; serves on the international advisory board of Archives of Neurology and Experimental Neurology; has received speaker honoraria from Bayer Schering, Novartis, Biogen Idec, Merck Serono, F. Hoffmann-La Roche Ltd. and Teva Pharmaceutical Industries Ltd.; has received research support from Biogen Idec, Bayer Schering, Merck Serono, Five Prime Therapeutics Inc., Metanomics, Chugai Pharmaceuticals and Novartis; and has filed a patent for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and genetic determinants of neutralising antibodies to interferon-beta.

Kottil Rammohan has received honoraria for participating in advisory boards and consulting for Acorda, Biogen Idec, EMD Serono, Genentech/F. Hoffmann-La Roche Ltd., Genzyme and Teva; he has also received grants from Accera, NIH and NMSS.

Gavin Giovannoni has received honoraria from Abbvie, Bayer HealthCare, Biogen, Canbex, FivePrime, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Synthon, Teva Neuroscience, UCB, and Vertex; research grant support from Biogen, Ironwood, Merck Serono, Merz, and Novartis; and compensation from Elsevier as co−Chief Editor of MS and Related Disorders.

Jerome de Seze has nothing to declare.

Amit Bar-Or has received personal compensation for consulting, serving on scientific advisory boards and/or speaking activities from Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly, Genentech Inc., GSK, Guthy-Jackson/GGF, Merck Serono, Novartis, Ono Pharmacia, F. Hoffmann-La Roche Ltd., Sanofi-Aventis, Teva Neuroscience and Wyeth.

Douglas Arnold reports equity interest in NeuroRx Research, which performed the MRI analysis for the trial, and consultation fees from Acorda, Biogen Idec, Genzyme, F. Hoffmann-La Roche Ltd., Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Novartis, Receptos, Sanofi-Aventis and Teva.

Annette Sauter is an employee and/or shareholder of F. Hoffmann-La Roche Ltd.

Algirdas Kakarieka is an employee and/or shareholder of F. Hoffmann-La Roche Ltd.

Donna Masterman is an employee of Genentech Inc., a member of the Roche Group.

Peter Chin is an employee of Genentech Inc., a member of the Roche Group.

Hideki Garren is an employee and/or shareholder of F. Hoffmann-La Roche Ltd.

Jerry Wolinsky has received compensation for service on steering committees or data monitoring boards for Novartis, F. Hoffmann-La Roche Ltd., Genzyme and Teva Pharmaceuticals; consultant fees from AbbVie, Actelion, Alkermes, Athersys Inc., EMD Serono, Forward Pharma, Genentech Inc., Genzyme (Sanofi), Novartis, F. Hoffmann-La Roche Ltd., Teva and XenoPort; and research support from Genzyme, Sanofi, the NIH and the NMSS through the University of Texas Health Science Center at Houston (UTHSCH) and royalties for monoclonal antibodies out-licensed to Chemicon International through UTHSCH.
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