Donna Masterman

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

BACKGROUND An 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. METHODS In 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. RESULTS The 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 was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25‐foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2‐weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain‐volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36‐Item Short‐Form Health Survey. Infusion‐related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long‐term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann–La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570.)

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

BACKGROUND B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS In 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. RESULTS The 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 disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium‐enhancing lesions per T1‐weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta‐1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper‐limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta‐1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion‐related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta‐1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta‐1a. CONCLUSIONS Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta‐1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann–La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333, respectively.)

Revision of the criteria for Alzheimer's disease: A symposium

The current criteria for classification of Alzheimers disease (AD) have deficiencies that limit drug development, research, and practice. The current standard for the clinical diagnosis of AD, the National Institute of Neurological and Communicative Disorders and Stroke (now known as the National Institute of Neurological Disorders and Stroke), and the Alzheimers Disease and Related Disorders Association (now known as the Alzheimers Association) criteria, are nearly 25 years old and have not been revised to incorporate advances in the epidemiology and genetics of AD, studies of clinicopathologic correlations and recent studies of potential diagnostic biomarkers. In a very real sense our ability to diagnose AD with a very high level of certainty has outpaced our current diagnostic criteria. The Alzheimers Association Research Roundtable convened a meeting in April 2009 to discuss new data and technologies that could, with further development, enable improvements in the clinical diagnosis of AD, especially in its earliest and mildest stages. This meeting reviewed the current standards for detecting and defining the clinical presentation of AD and discussed areas that could contribute to earlier and more accurate definitive clinical diagnosis. These included clinical, neuropsychological, and other performance‐based assessments, genetic contributions, and biochemical and neuroimaging biomarkers that could reflect AD pathology and lead to better ascertainment of AD, mild cognitive impairment, and presymptomatic AD.

Evaluation of no evidence of progression or active disease (nepad) in patients with primary progressive multiple sclerosis in the oratorio trial

Objectives To assess the effect of ocrelizumab from baseline to Week 120 on the proportion of patients with no evidence of progression or active disease (NEPAD) in the Phase III, placebo-controlled ORATORIO study in primary progressive multiple sclerosis (PPMS). PPMS is characterised by steadily increasing neurologic disability. The analysis of accompanying inflammatory disease activity in PPMS, including brain MRI activity and relapses, has to date been limited. NEPAD is a novel composite endpoint that assesses the combined absence of disease progression and active disease in patients with PPMS. Methods In a post-hoc exploratory analysis of the ORATORIO trial, 234 placebo- and 465 ocrelizumab-treated patients were evaluated to assess the proportion of patients with NEPAD, defined as having no evidence of progression (no 12 weeks confirmed progression of ≥1/≥0.5 points on the Expanded Disability Status Scale if the baseline score was ≤5.5/>5.5 points, respectively; no 12 weeks confirmed progression of ≥20% on the timed 25 foot walk test and 9-hole peg test), no brain MRI activity (no new/enlarging T2 lesions and no T1 Gd+ lesions), and no protocol-defined relapse. Brain MRI assessments were conducted at baseline and weeks 24, 48, and 120. Results Compared with placebo, ocrelizumab increased the proportion of patients with NEPAD at Week 120 (9.4% vs 29.9%; risk ratio ocrelizumab vs placebo (95% CI): 3.15 (2.07 to 4.79); p<0.0001). A consistent effect of ocrelizumab was also observed on all three components of NEPAD. Sensitivity analyses will also be presented. Conclusions In the ORATORIO trial, ocrelizumab increased by approximately 3-fold the proportion of patients with NEPAD vs placebo, as measured by the combination of no evidence of progression, no relapse and no MRI activity. NEPAD may represent a useful composite outcome to assess the absence of clinical and MRI features of disease progression and activity in patients with PPMS.