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Stephen L Hauser - One of the best experts on this subject based on the ideXlab platform.

  • Ocrelizumab in relapsing and primary progressive multiple sclerosis pharmacokinetic and pharmacodynamic analyses of opera i opera ii and oratorio
    British Journal of Clinical Pharmacology, 2021
    Co-Authors: Ekaterina Gibiansky, Ludwig Kappos, Stephen L Hauser, Claire Petry, Francois Mercier, Andreas Gunther, Ann Herman, Yumi Yamamoto, Qing Wang, Fabian Model
    Abstract:

    Aims Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of Ocrelizumab in patients with RMS or PPMS patients were assessed. Methods A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation. Results The Ocrelizumab serum concentration vs. time course was accurately described by a two-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing 90 kg when compared with the 60-90 kg group. The terminal half-life of Ocrelizumab was estimated as 26 days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing Ocrelizumab exposure. Conclusions The pharmacokinetics of Ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

  • 177 updated safety analysis of Ocrelizumab in multiple sclerosis
    Journal of Neurology Neurosurgery and Psychiatry, 2019
    Co-Authors: Carolyn A Young, Ludwig Kappos, Xavier Montalban, Stephen L Hauser, Richard Hughes, Harold Koendgen, John Mcnamara, Ashish Pradhan, David Wormser, Jerry S Wolinsky
    Abstract:

    Background Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of Ocrelizumab in patients with multiple sclerosis (MS). The safety/efficacy of Ocrelizumab have been characterised in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). We report ongoing safety evaluations from Ocrelizumab clinical trials and open-label extension periods up to February 2018. Methods Safety outcomes were reported for the Ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb MS trials. The number of post-marketing Ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented. Results In clinical trials, 3,811 patients with MS received Ocrelizumab (10,919 PY of exposure, as of February 2018). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 242 (239–245); serious AEs, 7.23 (6.73–7.75); infections, 74.5 (72.9–76.1); serious infections, 2.00 (1.74–2.28); and malignancy 0.45 (0.33–0.60). Updated post-marketing data will be presented. Conclusions Reported rates of events in the Ocrelizumab all-exposure population continue to be generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue. Disclosures Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.

  • 178 long term efficacy of Ocrelizumab in relapsing multiple sclerosis
    Journal of Neurology Neurosurgery and Psychiatry, 2019
    Co-Authors: Gavin Giovannoni, Xavier Montalban, Stephen L Hauser, Jerry S Wolinsky, Fabian Model, Bruno Brochet, Robert T Naismith, Stanislas Hubeaux, Lahar R Mehta, Ludwig Kappos
    Abstract:

    Background The efficacy and safety of Ocrelizumab in relapsing multiple sclerosis were demonstrated in the double-blind control period of the Phase III OPERA I/II trials (NCT01247324/NCT01412333). Here we assessed the efficacy of switching to or maintaining Ocrelizumab therapy after 3 years’ follow-up in the open-label extensions (OLEs) of these studies. Methods At OLE commencement, patients continued Ocrelizumab (OCR-OCR) or switched from interferon-β-1a (IFN) to Ocrelizumab (IFN-OCR). Adjusted annualised relapse rate (ARR) and time-to-onset of 24-week confirmed disability progression (CDP24) were analysed. Results Among IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08 and 0.07 at Years 1, 2 and 3 post-switch. OCR-OCR continuers maintained low ARRs through the year pre-OLE and the 3 years of OLE (0.13, 0.11, 0.08, 0.07). CDP24 was less frequent in OCR-OCR continuers versus IFN-OCR switchers in the year pre-switch and Years 1, 2 and 3 of OLE (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1% and 16.1%/21.3%; p Conclusions Switching from IFN to Ocrelizumab at the start of the OLE provided rapid reductions in ARR, maintained throughout the 3-year follow-up. After 5 years’ follow-up, patients who initiated Ocrelizumab 2 years earlier accrued significant, sustained reductions in disability progression compared with patients switching from IFN. Disclosures Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.

  • Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis results from the phase 3 randomized opera i opera ii and oratorio studies
    Multiple sclerosis and related disorders, 2019
    Co-Authors: Lori Mayer, Ludwig Kappos, K Rammohan, Stephen L Hauser, Anthony Traboulsee, Laura Julian, Julie Napieralski, Michael K Racke, Harold Kondgen, Hanzhe Zheng
    Abstract:

    Abstract Background Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20+ B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). Methods OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the Ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the Ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of Ocrelizumab or placebo. Results Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (Ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (Ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of Ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (Ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (Ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of Ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of Ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an Ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. Conclusion Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with Ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.

  • pharmacokinetics pharmacodynamics and exposure response analyses of Ocrelizumab in patients with multiple sclerosis n4 001
    Neurology, 2019
    Co-Authors: Heidemarie Kletzl, Ludwig Kappos, Ekaterina Gibiansky, Claire Petry, Francois Mercier, Qing Wang, Fabian Model, Andreas Guenther, Stephen L Hauser
    Abstract:

    Objective: To describe the population pharmacokinetics, pharmacodynamics, and exposure-efficacy/safety relationships of Ocrelizumab in patients with multiple sclerosis (MS). Background: Ocrelizumab is a CD20+ B cell-selective monoclonal antibody approved for treatment of relapsing MS (RMS) and primary progressive MS (PPMS). Design/Methods: Ocrelizumab Phase II/III data were analyzed using a non-linear mixed-effects model to describe Ocrelizumab pharmacokinetics and assess covariate effects. Exposure-response relationships for clinical efficacy (annualised relapse rate [ARR], 12-/24-week confirmed disability progression [CDP]) and safety parameters (serious adverse events, serious infections, infusion related reactions) were assessed. Results: A two-compartment model with time-dependent clearance and body weight as main covariate described accurately Ocrelizumab pharmacokinetics in patients with RMS (N=941) and PPMS (N=482). Exposure (area under the serum concentration–time curve) was 26% higher in patients with RMS 90kg versus a 75kg reference patient. Blood B-cell depletion correlated with Ocrelizumab exposure. Patients with RMS obtained similar benefit with regards to ARR independent of exposure, however, risk reductions in 12-/24-week CDP was exposure-dependent in patients with RMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.77, 0.80, 0.45 and 0.33 versus interferon-beta 1a, respectively) and PPMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.87, 0.83, 0.78 and 0.59 versus placebo, respectively). All safety parameters assessed were similar across the exposure quartiles. Conclusions: Higher Ocrelizumab exposure led to greater B-cell depletion. Clinical benefit on ARR was independent of exposure, but greater risk reduction in CDP was observed with higher Ocrelizumab exposure in patients with RMS and PPMS, suggesting that higher Ocrelizumab exposure (and greater B-cell depletion) is important for control of disability progression. The fact that effects are more pronounced in patients in higher exposure groups indicates that the current approved dose is closer to the lower part of the dose-response curve. The safety profile was similar across all exposure quartiles. Disclosure: Dr. Kletzl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche. Dr. Kletzl holds stock and/or stock options in F. Hoffmann-La Roche which sponsored research in which Dr. Kletzl was involved as an investigator. Dr. Kletzl holds stock and/or stock options in F. Hoffmann-La Roche. Dr. Kletzl has received research support from F. Hoffmann-La Roche. Dr. Gibiansky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffman-La Roche Ltd. Dr. Petry has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche Ltd. Dr. Mercier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche Ltd. Dr. Guenther has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F.Hoffmann-La Roche Ltd. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffman-La Roche Ltd. Dr. Model has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Kappos’ institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi-Aventis, Santhera, Teva and Vianex, and license fees for Neurostatus-UHB products. Dr. Kappos’ institution has received research support from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations. Dr. Hauser has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Annexon, Symbiotix, Bionure and Neurona; he has also received travel reimbursement from F. Hoffmann-La Roche Ltd and Novartis for CD20-related meetings and presentation.

Amit Baror - One of the best experts on this subject based on the ideXlab platform.

  • onset of clinical and mri efficacy of Ocrelizumab in relapsing multiple sclerosis
    Neurology, 2019
    Co-Authors: Frederik Barkhof, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Jian Han, Jerry S Wolinsky, Shibeshih Belachew, Laura Julian, Annette Sauter, Julie Napieralski
    Abstract:

    OBJECTIVE: To assess the onset of Ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, Ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving Ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg). RESULTS: In patients with RRMS, Ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, Ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks. CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with Ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and RMS, Ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

  • interim analysis of the oboe Ocrelizumab biomarker outcome evaluation study in multiple sclerosis ms s24 002
    Neurology, 2018
    Co-Authors: Amit Baror, Jeffrey M. Gelfand, Hanzhe Zheng, Ann Herman, Damian Fiore, Christopher Harp, B Musch, Anne H Cross
    Abstract:

    Objective: To provide interim analysis of the Ocrelizumab cerebrospinal fluid (CSF) and blood biomarker study (OBOE, NCT02688985) in multiple sclerosis (MS). Background: CSF biomarkers, including neurofilament light chain (NfL) and lymphocyte numbers, are potential indicators of central nervous system status and may improve understanding of MS disease pathways and therapeutic mechanisms of action. Design/Methods Patients with relapsing (RMS) or primary progressive MS receive Ocrelizumab 600 mg every 24 weeks. CSF is obtained by lumbar puncture (LP) before and at 12, 24, or 52 weeks after Ocrelizumab treatment; an RMS control arm receives 2 LPs 12 weeks apart before starting Ocrelizumab. Biomarkers are reported in RMS patients with pre-Ocrelizumab and 12-week (Arm 1) and 24-week (Arm 2) post-Ocrelizumab CSF available for interim analysis as of a June 1, 2017 clinical cutoff date (n=40). Safety data for all enrolled patients as of the cutoff is presented (n=82). Results: CSF samples from Weeks 12 and 24 post-Ocrelizumab treatment exhibited reductions in median concentration of NfL (−24%, −47%); median number of CD19+ B cells (−86%, −82%) and median number of CD3+ T cells (−60%, −67%). Ocrelizumab was generally well tolerated, consistent with safety in the Phase 3 studies. Infusion-related reactions (44%) and 1 serious adverse event (seizure) were reported. No serious infections, malignancies or deaths were reported. Conclusions: NfL decreased at 12 weeks, appeared to decrease further at 24 weeks, and correlated with CSF B and T cell numbers, suggesting continued reduction in axonal injury with Ocrelizumab treatment, and that levels of CSF inflammatory cells may predict neuronal injury. A single dose of Ocrelizumab reduced but did not completely deplete CSF B cells while also reducing CSF T cells, indicating B cells may function in T-cell antigen presentation, recruitment and/or maintenance in the CSF. The trial is continuing, with final results expected in early 2019. Study Supported by: Sponsored by Genentech, Inc. Disclosure: Dr. Bar-Or has nothing to disclose. Dr. Gelfand has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with . Dr. Fiore has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Harp has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Zheng has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Compensation from Genentech and stock in F. Hoffmann-La Roche Ltd as Genentech employee. Dr. Herman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Musch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genentech. Dr. Cross has received personal compensation for activities with AbbVie, BAYER, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and Teva. Dr. Cross has received research support for Genentech/ Roche.

  • effect of Ocrelizumab on vaccine responses in patients with multiple sclerosis s36 002
    Neurology, 2018
    Co-Authors: Daniela Stokmaier, John Mcnamara, Kevin L Winthrop, Cathy Chognot, Joanna Evershed, Marianna Manfrini, Amit Baror
    Abstract:

    Objective: VELOCE (NCT02545868) is a randomized, open-label, Phase IIIb study to assess if Ocrelizumab recipients with relapsing multiple sclerosis (RMS) raise adequate humoral responses to selected vaccines. Background: Ocrelizumab selectively depletes CD20+ B cells while preserving the capacity for pre-existing humoral immunity. Vaccinations against infections are an important part of the management of patients with MS. Design/Methods: Patients (N=102) were randomized 2:1 into Group A (n=68), receiving a single dose of Ocrelizumab 600 mg; or Control Group B (n=34), on no disease-modifying therapy or interferon-beta. All patients received a tetanus toxoid-containing vaccine, keyhole limpet hemocyanin (KLH), and a 23-valent pneumococcal polysaccharide vaccine (23-PPV). At randomization, Group A was subdivided into Groups A1 (n=33), receiving pneumococcal booster vaccine (13-PCV) 4 weeks after 23-PPV, and A2 (n=35), receiving seasonal influenza vaccine. Group B was treated the same as Group A2. Vaccinations in Group A started 12 weeks after Ocrelizumab treatment start, and in Group B on Day 1 Results: Positive response (% of patients; definition of response included in poster) to tetanus vaccine at 8 weeks was 23.9% in Group A (Ocrelizumab) versus 54.5% in Group B (control). Positive response to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in Group A (Ocrelizumab) and 100% in Group B (control). In Group A1 (Ocrelizumab), booster vaccine (13-PCV) did not enhance the response to 12 serotypes in common with 23-PPV. The humoral response to the neoantigen KLH was decreased in Group A (Ocrelizumab) versus Group B (control) at all time points measured. Seroprotective titers at 4 weeks against five influenza strains (season 2015/2016 and 2016/2017) ranged from 55.6% to 80.0% in Group A2 (Ocrelizumab) and 75.0% to 97.0% in Group B (control). Conclusions: As expected, Ocrelizumab attenuated the humoral response to the studied vaccines. Study Supported by: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Health Interactions, USA, and Articulate Science, UK. Disclosure: Dr. Stokmaier has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of F. Hoffman-La Roche Ltd. Dr. Winthrop has nothing to disclose. Dr. Chognot has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Evershed has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Yes - employment at Roche Products Ltd and shareholder of F. Hoffman-La Roche Ltd. Dr. Manfrini has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of F. Hoffman-La Roche Ltd. Dr. McNamara has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche LtdYES (I am a contract statistician, and have provided my services to Roche during the past year). Dr. McNamara has received compensation for serving on the Board of Directors of YES (I run my own very small freelance contract statistician business, John McNamara Consulting Limited, and I am a director of this business. My wife is a director also. There are no other directors or employees). Dr. Bar-Or has nothing to disclose.

  • po129 neda analysis by epoch in the opera studies of Ocrelizumab
    Journal of Neurology Neurosurgery and Psychiatry, 2017
    Co-Authors: Gavin Giovannoni, Ludwig Kappos, Amit Baror, Fred D. Lublin, Douglas L Arnold, Anthony Traboulsee, Jian Han, Shibeshih Belachew, Eva Havrdova, Stephen L Hauser
    Abstract:

    Background No Evidence of Disease Activity (NEDA) measures the absence of detectable clinical and magnetic resonance imaging (MRI) disease activity in relapsing multiple sclerosis. NEDA analyses using re-baselining may better reflect the effects of disease-modifying treatments. Objective To assess the effect of Ocrelizumab on NEDA by epoch in the pooled OPERA I/II (NCT01247324/NCT01412333) studies. Methods Patients received Ocrelizumab 600 mg every 24 weeks or subcutaneous interferon beta-1a (IFNβ−1a) 44 µg three-times weekly for 96 weeks. Brain MRI was undertaken at baseline and Weeks 24, 48, and 96. NEDA (i.e., the absence of protocol-defined relapses, 12 week confirmed disability progression, new/enlarging T2 lesions and T1 gadolinium-enhancing lesions) was assessed from baseline-Week 96, baseline-Week 48, Week 48 Week 96, baseline-Week 24 and Week 24 Week 96. Results Over 96 weeks, Ocrelizumab was associated with a 75% increase in the proportion of patients with NEDA versus IFNβ−1a (p Conclusions A higher proportion of patients reached NEDA at first MRI (Week 24) with Ocrelizumab versus IFNβ−1a; after re-baselining from Week 24–96, the proportion reaching NEDA increased further.

  • effects of Ocrelizumab on neurofilament light chain and other biomarkers of neuroinflammation and neurodegeneration in ms oboe study design p6 337
    Neurology, 2017
    Co-Authors: Ann Herman, Donna Masterman, Jian Han, Damian Fiore, Christopher Harp, B Musch, Anne H Cross, Beverly Assman, Amit Baror
    Abstract:

    Objective: To describe the design and status of the exploratory OBOE (Ocrelizumab Biomarker Outcome Evaluation) study (NCT02688985), which aims to further elucidate the mechanism of action (MOA) of Ocrelizumab and its effects on B and T cells in patients with relapsing (RMS) and primary progressive multiple sclerosis (PPMS). Background: Biomarkers such as neurofilament light chain (NfL) and other cerebrospinal fluid (CSF) measures may improve understanding of MS pathogenesis and the MOA of disease-modifying therapies. Design/Methods: Treatment-naive or previously treated patients with RMS or PPMS, aged 18–55 years, from the USA, Canada, Sweden, and Germany are eligible for enrollment. Patients with RMS will be required to have a screening Expanded Disability Status Scale score of 0–5.5 and active disease (≥1 clinical documented relapse, T1 gadolinium-enhancing lesion, or new T2 lesion) in the year before enrollment. Patients with RMS will initially receive two intravenous infusions of Ocrelizumab 300 mg separated by 14 days, followed by single 600 mg infusions at Weeks 24 and 48. Patients with PPMS will receive Ocrelizumab 600 mg (two intravenous infusions of 300 mg separated by 14 days) every 6 months over 48 weeks. Primary endpoints include changes in serial CSF measures of NfL, CD19 + B cells, and CD3 + T cells sampled prior to Ocrelizumab and at month 3, 6, or 12 during Ocrelizumab treatment. Longitudinal CSF assessments will also be performed in a subset of RMS patients while on disease-modifying therapy prior to receiving Ocrelizumab (‘Ocrelizumab delayed start’). Results: Planned enrollment includes 88 patients with RMS (including 16 Ocrelizumab delayed start) and 16 with PPMS. Updated status and information regarding biomarker assays will be reported. Conclusions: OBOE will provide important information on putative disease biomarkers in RMS and PPMS, and the effect of selectively depleting CD20 + B cells on those markers. Study Supported by: Sponsored by Genentech, Inc. Disclosure: Dr. Herman has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Herman holds stock and/or stock options in Roche. Dr. Musch has received personal compensation for activities with Genentech Inc. as an employee. Dr. Musch holds stock and/or stock options in Genentech Inc. Dr. Harp has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Harp holds stock and/or stock options in Genetech, Inc. Dr. Han has received personal compensation for activities with F. Hoffmann-La Roche Ltd. and Genentech Inc. as an employee. Dr. Han holds stock and/or stock options in Genetech Inc. Dr. Assman has received personal compensation for activities with F. Hoffman-La Roche Ltd. and Genentech, Inc. as an employee. Dr. Assman holds stock and/or stock options in F. Hoffman-La Roche Ltd. and Genentech. Dr. Fiore has received personal compensation for activities with F. Hoffmann-La Roche Ltd. and Genentech Inc., as an employee. Dr. Masterman has received personal compensation for activities with Genentech as an employee. Dr. Masterman holds stock and/or stock options in Genentech. Dr. Cross has received personal compensation for activities with AbbVie, Biogen, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, and Teva Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, and Eli Lilly for consulting, serving on scientific advisory boards and/or as a speaker.

Ludwig Kappos - One of the best experts on this subject based on the ideXlab platform.

  • Ocrelizumab in relapsing and primary progressive multiple sclerosis pharmacokinetic and pharmacodynamic analyses of opera i opera ii and oratorio
    British Journal of Clinical Pharmacology, 2021
    Co-Authors: Ekaterina Gibiansky, Ludwig Kappos, Stephen L Hauser, Claire Petry, Francois Mercier, Andreas Gunther, Ann Herman, Yumi Yamamoto, Qing Wang, Fabian Model
    Abstract:

    Aims Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of Ocrelizumab in patients with RMS or PPMS patients were assessed. Methods A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation. Results The Ocrelizumab serum concentration vs. time course was accurately described by a two-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing 90 kg when compared with the 60-90 kg group. The terminal half-life of Ocrelizumab was estimated as 26 days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing Ocrelizumab exposure. Conclusions The pharmacokinetics of Ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

  • 177 updated safety analysis of Ocrelizumab in multiple sclerosis
    Journal of Neurology Neurosurgery and Psychiatry, 2019
    Co-Authors: Carolyn A Young, Ludwig Kappos, Xavier Montalban, Stephen L Hauser, Richard Hughes, Harold Koendgen, John Mcnamara, Ashish Pradhan, David Wormser, Jerry S Wolinsky
    Abstract:

    Background Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of Ocrelizumab in patients with multiple sclerosis (MS). The safety/efficacy of Ocrelizumab have been characterised in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). We report ongoing safety evaluations from Ocrelizumab clinical trials and open-label extension periods up to February 2018. Methods Safety outcomes were reported for the Ocrelizumab all-exposure population in Phase II/III and ongoing Phase IIIb MS trials. The number of post-marketing Ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented. Results In clinical trials, 3,811 patients with MS received Ocrelizumab (10,919 PY of exposure, as of February 2018). Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 242 (239–245); serious AEs, 7.23 (6.73–7.75); infections, 74.5 (72.9–76.1); serious infections, 2.00 (1.74–2.28); and malignancy 0.45 (0.33–0.60). Updated post-marketing data will be presented. Conclusions Reported rates of events in the Ocrelizumab all-exposure population continue to be generally consistent with the controlled treatment period in RMS/PPMS populations. Regular reporting of long-term safety data will continue. Disclosures Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.

  • 178 long term efficacy of Ocrelizumab in relapsing multiple sclerosis
    Journal of Neurology Neurosurgery and Psychiatry, 2019
    Co-Authors: Gavin Giovannoni, Xavier Montalban, Stephen L Hauser, Jerry S Wolinsky, Fabian Model, Bruno Brochet, Robert T Naismith, Stanislas Hubeaux, Lahar R Mehta, Ludwig Kappos
    Abstract:

    Background The efficacy and safety of Ocrelizumab in relapsing multiple sclerosis were demonstrated in the double-blind control period of the Phase III OPERA I/II trials (NCT01247324/NCT01412333). Here we assessed the efficacy of switching to or maintaining Ocrelizumab therapy after 3 years’ follow-up in the open-label extensions (OLEs) of these studies. Methods At OLE commencement, patients continued Ocrelizumab (OCR-OCR) or switched from interferon-β-1a (IFN) to Ocrelizumab (IFN-OCR). Adjusted annualised relapse rate (ARR) and time-to-onset of 24-week confirmed disability progression (CDP24) were analysed. Results Among IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08 and 0.07 at Years 1, 2 and 3 post-switch. OCR-OCR continuers maintained low ARRs through the year pre-OLE and the 3 years of OLE (0.13, 0.11, 0.08, 0.07). CDP24 was less frequent in OCR-OCR continuers versus IFN-OCR switchers in the year pre-switch and Years 1, 2 and 3 of OLE (7.7%/12.0%, 10.1%/15.6%, 13.9%/18.1% and 16.1%/21.3%; p Conclusions Switching from IFN to Ocrelizumab at the start of the OLE provided rapid reductions in ARR, maintained throughout the 3-year follow-up. After 5 years’ follow-up, patients who initiated Ocrelizumab 2 years earlier accrued significant, sustained reductions in disability progression compared with patients switching from IFN. Disclosures Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd.

  • onset of clinical and mri efficacy of Ocrelizumab in relapsing multiple sclerosis
    Neurology, 2019
    Co-Authors: Frederik Barkhof, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Jian Han, Jerry S Wolinsky, Shibeshih Belachew, Laura Julian, Annette Sauter, Julie Napieralski
    Abstract:

    OBJECTIVE: To assess the onset of Ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, Ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving Ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg). RESULTS: In patients with RRMS, Ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, Ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks. CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with Ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and RMS, Ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

  • Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis results from the phase 3 randomized opera i opera ii and oratorio studies
    Multiple sclerosis and related disorders, 2019
    Co-Authors: Lori Mayer, Ludwig Kappos, K Rammohan, Stephen L Hauser, Anthony Traboulsee, Laura Julian, Julie Napieralski, Michael K Racke, Harold Kondgen, Hanzhe Zheng
    Abstract:

    Abstract Background Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20+ B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS). Methods OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the Ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the Ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of Ocrelizumab or placebo. Results Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (Ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (Ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of Ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (Ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (Ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of Ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of Ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an Ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs. Conclusion Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with Ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.

Hans-peter Hartung - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up from the oratorio trial of Ocrelizumab for primary progressive multiple sclerosis a post hoc analysis from the ongoing open label extension of the randomised placebo controlled phase 3 trial
    Lancet Neurology, 2020
    Co-Authors: Jerry S Wolinsky, Hans-peter Hartung, Xavier Montalban, Douglas L Arnold, Harold Koendgen, Bruno Brochet, Robert T Naismith, Marianna Manfrini, James Overell, Annette Sauter
    Abstract:

    Summary Background The safety and efficacy of Ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to Ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO. Methods ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18–55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0–6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of Ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued Ocrelizumab or switched from placebo to Ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov , NCT01194570 , and is ongoing. Findings From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the Ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated Ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9–21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1–20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [–0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6–16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8–13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated Ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p Interpretation Compared with patients switching from placebo, earlier and continuous Ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with Ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods. Funding F Hoffmann-La Roche.

  • onset of clinical and mri efficacy of Ocrelizumab in relapsing multiple sclerosis
    Neurology, 2019
    Co-Authors: Frederik Barkhof, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Jian Han, Jerry S Wolinsky, Shibeshih Belachew, Laura Julian, Annette Sauter, Julie Napieralski
    Abstract:

    OBJECTIVE: To assess the onset of Ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, Ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving Ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg). RESULTS: In patients with RRMS, Ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, Ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks. CONCLUSION: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with Ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS and RMS, Ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

  • Ocrelizumab versus interferon beta 1a in relapsing multiple sclerosis
    The New England Journal of Medicine, 2017
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Bernhard Hemmer, Amit Baror, Gavin Giovannoni, Xavier Montalban, K Rammohan, Fred D. Lublin, Giancarlo Comi, Krzysztof Selmaj
    Abstract:

    BackgroundB cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. MethodsIn two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous Ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. ResultsThe annualized relapse rate was lower with Ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with Ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with Ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disabilit...

  • Ocrelizumab versus placebo in primary progressive multiple sclerosis
    The New England Journal of Medicine, 2017
    Co-Authors: Xavier Montalban, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Gavin Giovannoni, Stephen L Hauser, Giancarlo Comi, Douglas L Arnold, Jérôme De Seze, Bernhard Hemmer
    Abstract:

    BackgroundAn evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied Ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. MethodsIn this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous Ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. ResultsThe percentage of patients with 12-week confirmed disability progression was 32.9% with Ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression w...

  • efficacy of Ocrelizumab in patients with relapsing multiple sclerosis pooled analysis of two identical phase iii double blind double dummy interferon beta 1a controlled studies s49 003
    Neurology, 2016
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Amit Baror, Krzysztof Selmaj, Fred D. Lublin, Giancarlo Comi, Douglas L Arnold, Anthony Traboulsee, Gaelle Klingelschmitt, Donna Masterman
    Abstract:

    Objective To evaluate the efficacy of Ocrelizumab compared with interferon beta-1a (IFNβ-1a) through pooled analysis of efficacy in OPERA I and OPERA II. Background MS pathogenesis is understood to involve two distinct, but overlapping mechanisms, with early inflammation and concurrent or subsequent neurodegeneration. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20 + B cells, was superior in reducing annualized relapse rate (ARR) vs IFNβ-1a in OPERA I and OPERA II, two identical Phase III, randomized, double-blind, double-dummy trials in relapsing MS. Methods Pooled analyses of OPERA I and OPERA II efficacy were considered to be valid if treatment differences between the Ocrelizumab and IFNβ-1a groups for ARR through week 96 and ≥12-week confirmed disability progression (CDP) were broadly consistent between the two studies; i.e. p>0.1 for study-by-treatment group interaction or p≤0.1 for study-by-treatment group interaction and both within-study treatment differences point to the same direction. Pre-specified pooled analyses included ≥12-week and ≥24-week CDP and ≥12-week confirmed disability improvement (CDI) through week 96. Results Consistency of baseline characteristics and treatment effects across both studies met pre-determined criteria for pooled efficacy analysis. Compared with IFNβ-1a, Ocrelizumab showed a 47[percnt] reduction in adjusted ARR (p<0.0001) and reduced the risk of 12-week CDP by 40[percnt] (p=0.0006) and 24-week CDP by 40[percnt] (p=0.0025). In pooled analyses, the proportion of Ocrelizumab-treated patients that achieved CDI at 12 and 24 weeks was 20.7[percnt] and 15.6[percnt] vs 15.6[percnt] and 11.6[percnt], respectively, for IFNβ-1a-treated patients, representing a 33[percnt] and 36[percnt] relative improvement (relative risk 1.33 [p=0.0194] and 1.36 [p=0.0343]), respectively. Ocrelizumab showed an 18.8[percnt] reduction in brain atrophy vs IFNβ-1a (p=0.0015). Conclusions Pooled analyses of OPERA I and OPERA II efficacy endpoints showed that Ocrelizumab significantly suppressed disease progression and increased the proportion of patients with disability improvement over 96 weeks compared with IFNβ-1a. Supported by F. Hoffmann-La Roche Disclosure: Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. Arnold holds stock and/or stock options in NeuroRx Research, which sponsored research in which Dr. Arnold was an investigator. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly as a consultant, speaker and advisory board member. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Hartung has received personal compensation for activities with from Bayer, Biogen, GeNeuro, Genzyme as speaker, committee member, consultant. Dr. Lublin has received personal compensation for activities with Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc.,Genzyme, Sanofi, Celgene, Cognition Pharmaceuticals, Inc., Elsevier, NIH, and NMSS. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Novartis, TEVA Pharmaceuticals, Roche Diagnostics Corporation, Genzyme, Synthon, Receptos, and Bayer for serving on the Scientific Advisory Board. Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai. Dr. Klingelschmitt holds stock and/or stock options in F. Hoffmann-La Roche, Ltd., which sponsored research in which Dr. Klingelschmitt was involved as an investigator. Dr. Masterman holds stock and/or stock options in Genentech, which sponsored research in which Dr. Masterman was involved as an investigator. Dr. Fontoura has received personal compensation for activities with.F. Hoffmann-La Roche as an employee. Dr. Chin has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Garren has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH.

Douglas L Arnold - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up from the oratorio trial of Ocrelizumab for primary progressive multiple sclerosis a post hoc analysis from the ongoing open label extension of the randomised placebo controlled phase 3 trial
    Lancet Neurology, 2020
    Co-Authors: Jerry S Wolinsky, Hans-peter Hartung, Xavier Montalban, Douglas L Arnold, Harold Koendgen, Bruno Brochet, Robert T Naismith, Marianna Manfrini, James Overell, Annette Sauter
    Abstract:

    Summary Background The safety and efficacy of Ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to Ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO. Methods ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18–55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0–6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of Ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued Ocrelizumab or switched from placebo to Ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov , NCT01194570 , and is ongoing. Findings From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the Ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated Ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9–21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1–20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [–0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6–16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8–13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated Ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p Interpretation Compared with patients switching from placebo, earlier and continuous Ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with Ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods. Funding F Hoffmann-La Roche.

  • po129 neda analysis by epoch in the opera studies of Ocrelizumab
    Journal of Neurology Neurosurgery and Psychiatry, 2017
    Co-Authors: Gavin Giovannoni, Ludwig Kappos, Amit Baror, Fred D. Lublin, Douglas L Arnold, Anthony Traboulsee, Jian Han, Shibeshih Belachew, Eva Havrdova, Stephen L Hauser
    Abstract:

    Background No Evidence of Disease Activity (NEDA) measures the absence of detectable clinical and magnetic resonance imaging (MRI) disease activity in relapsing multiple sclerosis. NEDA analyses using re-baselining may better reflect the effects of disease-modifying treatments. Objective To assess the effect of Ocrelizumab on NEDA by epoch in the pooled OPERA I/II (NCT01247324/NCT01412333) studies. Methods Patients received Ocrelizumab 600 mg every 24 weeks or subcutaneous interferon beta-1a (IFNβ−1a) 44 µg three-times weekly for 96 weeks. Brain MRI was undertaken at baseline and Weeks 24, 48, and 96. NEDA (i.e., the absence of protocol-defined relapses, 12 week confirmed disability progression, new/enlarging T2 lesions and T1 gadolinium-enhancing lesions) was assessed from baseline-Week 96, baseline-Week 48, Week 48 Week 96, baseline-Week 24 and Week 24 Week 96. Results Over 96 weeks, Ocrelizumab was associated with a 75% increase in the proportion of patients with NEDA versus IFNβ−1a (p Conclusions A higher proportion of patients reached NEDA at first MRI (Week 24) with Ocrelizumab versus IFNβ−1a; after re-baselining from Week 24–96, the proportion reaching NEDA increased further.

  • Ocrelizumab versus placebo in primary progressive multiple sclerosis
    The New England Journal of Medicine, 2017
    Co-Authors: Xavier Montalban, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Gavin Giovannoni, Stephen L Hauser, Giancarlo Comi, Douglas L Arnold, Jérôme De Seze, Bernhard Hemmer
    Abstract:

    BackgroundAn evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied Ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. MethodsIn this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous Ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. ResultsThe percentage of patients with 12-week confirmed disability progression was 32.9% with Ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression w...

  • efficacy of Ocrelizumab in patients with relapsing multiple sclerosis pooled analysis of two identical phase iii double blind double dummy interferon beta 1a controlled studies s49 003
    Neurology, 2016
    Co-Authors: Stephen L Hauser, Hans-peter Hartung, Amit Baror, Krzysztof Selmaj, Fred D. Lublin, Giancarlo Comi, Douglas L Arnold, Anthony Traboulsee, Gaelle Klingelschmitt, Donna Masterman
    Abstract:

    Objective To evaluate the efficacy of Ocrelizumab compared with interferon beta-1a (IFNβ-1a) through pooled analysis of efficacy in OPERA I and OPERA II. Background MS pathogenesis is understood to involve two distinct, but overlapping mechanisms, with early inflammation and concurrent or subsequent neurodegeneration. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20 + B cells, was superior in reducing annualized relapse rate (ARR) vs IFNβ-1a in OPERA I and OPERA II, two identical Phase III, randomized, double-blind, double-dummy trials in relapsing MS. Methods Pooled analyses of OPERA I and OPERA II efficacy were considered to be valid if treatment differences between the Ocrelizumab and IFNβ-1a groups for ARR through week 96 and ≥12-week confirmed disability progression (CDP) were broadly consistent between the two studies; i.e. p>0.1 for study-by-treatment group interaction or p≤0.1 for study-by-treatment group interaction and both within-study treatment differences point to the same direction. Pre-specified pooled analyses included ≥12-week and ≥24-week CDP and ≥12-week confirmed disability improvement (CDI) through week 96. Results Consistency of baseline characteristics and treatment effects across both studies met pre-determined criteria for pooled efficacy analysis. Compared with IFNβ-1a, Ocrelizumab showed a 47[percnt] reduction in adjusted ARR (p<0.0001) and reduced the risk of 12-week CDP by 40[percnt] (p=0.0006) and 24-week CDP by 40[percnt] (p=0.0025). In pooled analyses, the proportion of Ocrelizumab-treated patients that achieved CDI at 12 and 24 weeks was 20.7[percnt] and 15.6[percnt] vs 15.6[percnt] and 11.6[percnt], respectively, for IFNβ-1a-treated patients, representing a 33[percnt] and 36[percnt] relative improvement (relative risk 1.33 [p=0.0194] and 1.36 [p=0.0343]), respectively. Ocrelizumab showed an 18.8[percnt] reduction in brain atrophy vs IFNβ-1a (p=0.0015). Conclusions Pooled analyses of OPERA I and OPERA II efficacy endpoints showed that Ocrelizumab significantly suppressed disease progression and increased the proportion of patients with disability improvement over 96 weeks compared with IFNβ-1a. Supported by F. Hoffmann-La Roche Disclosure: Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd. Dr. Arnold holds stock and/or stock options in NeuroRx Research, which sponsored research in which Dr. Arnold was an investigator. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly as a consultant, speaker and advisory board member. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Hartung has received personal compensation for activities with from Bayer, Biogen, GeNeuro, Genzyme as speaker, committee member, consultant. Dr. Lublin has received personal compensation for activities with Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc.,Genzyme, Sanofi, Celgene, Cognition Pharmaceuticals, Inc., Elsevier, NIH, and NMSS. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Novartis, TEVA Pharmaceuticals, Roche Diagnostics Corporation, Genzyme, Synthon, Receptos, and Bayer for serving on the Scientific Advisory Board. Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai. Dr. Klingelschmitt holds stock and/or stock options in F. Hoffmann-La Roche, Ltd., which sponsored research in which Dr. Klingelschmitt was involved as an investigator. Dr. Masterman holds stock and/or stock options in Genentech, which sponsored research in which Dr. Masterman was involved as an investigator. Dr. Fontoura has received personal compensation for activities with.F. Hoffmann-La Roche as an employee. Dr. Chin has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Garren has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH.

  • Ocrelizumab no evidence of disease activity neda status at 96 weeks in patients with relapsing multiple sclerosis analysis of the phase iii double blind double dummy interferon beta 1a controlled opera i and opera ii studies pl02 004
    Neurology, 2016
    Co-Authors: Anthony Traboulsee, Ludwig Kappos, Hans-peter Hartung, Amit Baror, Krzysztof Selmaj, Fred D. Lublin, Giancarlo Comi, Douglas L Arnold, Gaelle Klingelschmitt, Donna Masterman
    Abstract:

    Objective: To evaluate the effect of Ocrelizumab vs interferon beta-1a (IFNβ-1a) on achieving no evidence of disease activity (NEDA) in patients with relapsing MS over 96 weeks in two identical Phase III, randomized, double-blind, double-dummy trials (OPERA I and OPERA II). Background: MS treatment goals are evolving with the emergence of higher-efficacy therapies. NEDA is a composite measure of the absence of clinical and MRI findings and a rapidly emerging treatment goal. Methods: In OPERA I and OPERA II, patients were randomized (1:1) to receive Ocrelizumab 600mg via intravenous infusion every 24 weeks or subcutaneous IFNβ-1a 44μg three-times weekly over 96 weeks. NEDA (defined as no relapses, confirmed disability progression [CDP], new/enlarging T2 lesions, or gadolinium-enhancing T1 lesions) was analyzed over 96 weeks. MRI was assessed at baseline, 24, 48, and 96 weeks. Results: At 96 weeks, 47.9[percnt] and 47.5[percnt] of Ocrelizumab-treated patients vs 29.2[percnt] and 25.1[percnt] of IFNβ-1a-treated patients achieved NEDA in OPERA I (64[percnt] increase; p<0.0001) and OPERA II (89[percnt] increase; p<0.001), respectively: 80.4[percnt] and 78.9[percnt] of Ocrelizumab-treated patients vs 66.7[percnt] and 64.5[percnt] of IFNβ-1a-treated were without relapses; 92.4[percnt] and 89.4[percnt] of Ocrelizumab-treated patients vs 87.8[percnt] and 84.9[percnt] of IFNβ-1a-treated were without CDP; 91.7[percnt] and 90.2[percnt] of Ocrelizumab-treated patients vs 69.8[percnt] and 63.9[percnt] of IFNβ-1a-treated were without gadolinium-enhancing T1 lesions; and 61.7[percnt] and 60.9[percnt] of Ocrelizumab-treated patients vs 38.7[percnt] and 38.0[percnt] of IFNβ-1a-treated were without new/enlarging T2 lesions in OPERA I and OPERA II, respectively. After week 24, ≥96.0[percnt] of all Ocrelizumab-treated patients compared with 60.8-70.9[percnt] of IFNβ1-a-treated patients were without new/enlarging T2 lesions. Conclusions: Ocrelizumab consistently resulted in greater achievement of NEDA vs IFNβ-1a over 96 weeks, with elimination of new/enlarging T2 lesions in nearly all patients after week 24. Supported by F. Hoffmann-La Roche Disclosure: Dr. Traboulsee has received personal compensation for activities with Genzyme and Roche. Dr. Traboulsee has received research support from Genzyme, Roche, Chugai. Dr. Arnold holds stock and/or stock options in NeuroRx Research, which sponsored research in which Dr. Arnold was an investigator. Dr. Bar-Or has received personal compensation for activities with Bayer, Bayhill Therapeutics, Berlex, Biogen Idec, BioMS, Diogenix, Eli Lilly as a consultant, speaker and advisory board member. Dr. Comi has received personal compensation for activities with Teva, Novartis, Genzyme, Merck Serono, Biogen, Bayer, Actelion, Almirall, and Serono Symposia International Foundation. Dr. Hartung has received personal compensation for activities with from Bayer, Biogen, GeNeuro, Genzyme as speaker, committee member, consultant. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH. Dr. Lublin has received personal compensation for activities with Acorda Therapeutics, Inc., Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc.,Genzyme, Sanofi, Celgene, Cognition Pharmaceuticals, Inc., Elsevier, NIH, and NMSS. Dr. Selmaj has received personal compensation for activities with Biogen Idec, Novartis, TEVA Pharmaceuticals, Roche Diagnostics Corporation, Genzyme, Synthon, Receptos, and Bayer for serving on the Scientific Advisory Board. Dr. Klingelschmitt holds stock and/or stock options in F. Hoffmann-La Roche, Ltd., which sponsored research in which Dr. Klingelschmitt was involved as an investigator. Dr. Masterman holds stock and/or stock options in Genentech, which sponsored research in which Dr. Masterman was involved as an investigator. Dr. Fontoura has received personal compensation for activities with.F. Hoffmann-La Roche as an employee. Dr. Chin has received personal compensation for activities with Genentech, Inc. as an employee. Dr. Garren has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Hauser has received personal compensation for activities with Annexon, Symbiotix, Bionure as a scientific advisory board member and from F. Hoffmann-La Roche Ltd.