Disclosures Jerry Wolinsky has served on advisory boards, data monitoring or Bernhard Hemmer has served on scientific advisory boards for F. steering committees, held consulting agreements, or received Hoffmann-La Roche Ltd., Novartis, Bayer Schering and Genentech; speaker honoraria from the following commercial entities: AbbVie, has received speaker honoraria from Biogen Idec and F. Hoffmann- AcademicCME, Alkermes, Antisense Therapeutics, Bayer HealthCare, La Roche Ltd.; has received research support from Chugai Forward Pharma A/S, medDay, Mapi Scientific, Novartis, Pharmaceuticals; holds part of a patent for the detection of Roche/Genentech, Sanofi Genzyme, Takeda, Teva Pharmaceuticals, antibodies and T cells against KIR4.1 in a subpopulation of MS patients WebMD. Royalties are received for out licensed monoclonal and genetic determinants of neutralising antibodies to interferon- antibodies through the UTHSCH to Millipore (Chemicon International) beta. Corporation since 1993. Kottil Rammohan has received honoraria for participating in advisory Douglas L Arnold reports equity interest in NeuroRx Research, which boards and consulting for Acorda, Biogen, EMD Serono, Genentech, Ocrelizumab Efficacy in PPMS Patients in the performed the MRI analysis for the trial, and consultation fees from Inc./F. Hoffmann-La Roche Ltd., Genzyme and Teva; he has also Acorda Therapeutics, Biogen, Genzyme, F. Hoffmann-La Roche Ltd, received grants from Accera, Novartis and the United States Presence/Absence of T1 Gadolinium-Enhancing Lesions at Innate Immunotherapeutics, MedImmune, Mitsubishi Pharma, Department of Defense. Novartis, Receptos, Sanofi Aventis, and Teva. Baseline in a Phase III Placebo-Controlled Trial Peter Chin is an employee and/or shareholder of Genentech, Inc. Amit Bar-Or has served on scientific advisory boards for F. Hoffmann- La Roche Ltd., Genentech, Biogen Idec, GlaxoSmithKline, Merck/EMD Paulo Fontura is an employee and shareholder of F. Hoffmann-La Serono, Medimmune, Mitsubishi Pharma, Ono Pharma, Receptos, Roche Ltd. Sanofi-Genzyme, and Guthy-Jackson/GGF; he has also received research support from Novartis and Sanofi-Genzyme. Hideki Garren is an employee and shareholder of F. Hoffmann-La Roche Ltd. Jérôme de Seze has received consultancy fees and served as an Donna Masterman is an employee and/or shareholder of expert for advisory boards for Alexion, Allergan, Almiral, Bayer, Genentech, Inc. Biogen, Chugai, CSL Behring, F. Hoffmann-La Roche Ltd., Genzyme, J Wolinsky, DL Arnold, A Bar-Or, J de Seze, G Giovannoni, B Hemmer, K Rammohan, LFB, Merck, Novartis, and Teva. Annette Sauter is an employee and shareholder of F. Hoffmann-La P Chin, P Fontoura, H Garren, D Masterman, A Sauter, X Montalban Gavin Giovannoni has received honoraria from AbbVie, Bayer Roche Ltd. HealthCare, Biogen, Canbex Therapeutics, Five Prime Therapeutics, on behalf of the ORATORIO clinical investigators Genzyme, GSK, GW Pharma, Merck, Merck Serono, Novartis, Protein Xavier Montalban has received speaking honoraria and travel Discovery Laboratories, F. Hoffmann-La Roche Ltd., Synthon, Teva expense reimbursement for participation in scientific meetings, has NCT01194570 Neuroscience, UCB and Vertex; research grant support from Biogen, been a steering committee member of clinical trials or participated in Ironwood, Merck Serono, Merz and Novartis; and compensation from advisory boards of clinical trials in the past years with Actelion, Elsevier. Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Octapharma, Receptos, F. Hoffmann-La Roche Ltd., Sanofi, Teva and Trophos. T he 2016 Annual Me e ting o f the Co nso rtium o f Multiple S c le ro sis Ce nte rs Natio nal Harbo r, MD, US A, June 1-4, 2016 Oral Pre se ntatio n DX06 The study was sponsored by F. Hoffmann-La Roche Ltd. Support for third-party writing assistance was provided by F. Hoffmann-La Roche Ltd, furnished by Articulate Science and Health Interactions. 2 Primary progressive multiple sclerosis (PPMS): Learning objectives Epidemiology and unmet needs • To review the primary and key secondary efficacy outcomes of ORATORIO, a randomized, parallel-group, double-blind, placebo-controlled Phase III study of ocrelizumab in primary progressive multiple sclerosis (PPMS) • To explore the efficacy of ocrelizumab versus placebo in PPMS patients with and without T1 gadolinium-enhancing lesions at baseline • PPMS is characterized • To assess the overall safety and benefit-risk profile of ocrelizumab versus • PPMS median age of by a progressive • More than 2.3 million placebo in PPMS patients in ORATORIO onset ≈ 40 years 5 course from people worldwide disease onset 3,4 affected by MS 1 • Men and women affected equally 5 • Relapses and • ≈ 10% have PPMS contrast-enhancing • No approved • No cure for MS 2 lesions may occur therapies for PPMS in PPMS 4 Previous trials have failed to demonstrate efficacy in slowing of • disability progression in patients with PPMS PPMS is a disabling condition with very high unmet medical need • MS, multiple sclerosis. 1. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf; 2. Markowitz CE, e t al. Am J Manag Care 2010;16:S211–S218; 3. Ebers GC. Mult S c le r 2004;10 Suppl 1:S8–13; discussion S13–S15; 4. Miller DH, Leary SM. L anc e t Ne uro l 2007;6:903–912; 3 4 5. Cottrell DA, e t al. Brain 1999;122 :625–639.
ORATORIO: Phase III PPMS ORATORIO: Study design Study objectives and endpoints Blinded Treatment Period Obje ctive s Minimum five 24-week treatment doses for a total of 120 weeks a • To evaluate the efficacy and safety of ocrelizumab compared with OCRELIZUMAB 600 mg IV infusions every 24 weeks b placebo in patients with PPMS Diagnosis of PPMS • 2:1 Randomization c (2005 revised McDonald criteria) 1 Age 18–55 years P r imar y e ndpoint • EDSS 3.0–6.5 • • 12-week confirmed disability progression (CDP) CSF: elevated IgG • index or >1 oligoclonal bands No history of RRMS, Se condar y e ndpoints • PLACEBO SPMS, or PRMS • 24-week CDP No treatment with • other MS DMTs at screening • Change in timed 25-foot walk PATIENTS DISCONTINUING TREATMENT ENTERED SAFETY FOLLOW-UP • Change in T2 lesion volume a The blinded treatment period continued until the last patient completed • Percent change in whole brain volume 120 weeks and target of 253 CDP events was reached. b Patients received methylprednisolone prior to each ocrelizumab infusion SAFETY FOLLOW-UP or placebo infusion. • SF-36 Physical Component Score ≥ 48 weeks from date of last infusion c 2:1 randomization stratified by age ( ≤ 45 vs >45) and region (USA vs ROW). d Continued monitoring occurred if B cells were not repleted. B-CELL MONITORING d BL, baseline; CDP, confirmed disability progression; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; IV, intravenous; MRI, magnetic resonance imaging; PPMS, primary progressive MS; PRMS, progressive-relapsing MS; ROW, rest of world; RRMS, relapsing-remitting MS; SPMS, secondary progressive MS. 5 PPMS, primary progressive multiple sclerosis; SF-36, short form (36). 6 1. Polman CH, e t al. Ann Ne uro l 2005;58:840–6. ORATORIO: Significant reduction in risk of 12-week confirmed MS disease history and baseline characteristics disability progression Overall Study Population (n=488) Placebo Ocrelizumab N=244 N=488 Age, years, mean (SD) 44.4 (8.3) 44.7 (7.9) Female, n (%) 124 (50.8) 237 (48.6) 24% Time since MS symptom onset, years, mean (SD) 6.1 (3.6) 6.7 (4.0) reduction in risk of CDP HR (95% CI): 0.76 (0.59, 0.98); Time since MS diagnosis, years, mean (SD) 2.8 (3.3) 2.9 (3.2) p-value (log rank)=0.03* MS disease-modifying treatment naïve,* n (%) 214 (87.7) 433 (88.7) EDSS, mean (SD) 4.7 (1.2) 4.7 (1.2) MRI Patients with T1 Gd + lesions, n (%) 60 (24.7) 133 (27.5) 10.9 (13.0) 12.7 (15.1) Brain T2 hyperintense lesion volume, cm 3 , mean (SD) 1469.9 (88.7) 1462.9 (83.9) Normalized brain volume, cm 3 , mean (SD) Evaluation of efficacy in patient subgroups with and without T1 gadolinium-enhancing lesions at baseline is a key area of interest Primary e ndpo int *No disease-modifying treatments in the previous 2 years. *Analysis based on ITT population; p-value based on log-rank test stratified by geographic region and age. Patients with initial disability EDSS, Expanded Disability Status Scale; Gd + , gadolinium-enhancing; MRI, magnetic resonance imaging; MS, multiple sclerosis; progression who discontinued treatment early with no confirmatory EDSS assessment were considered as having confirmed disability progression. SD, standard deviation. CDP, confirmed disability progression; CI, confidence interval; EDSS, Expanded Disability Status Scale; Gd + , gadolinium-enhancing; HR, hazard 7 ratio; ITT, intent-to-treat. 8
Recommend
More recommend
